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Breast Cancer
Updated: 08/26/2004

ABSTRACTS

American Cancer Society's Guide to Complementary and Alternative Cancer Methods.

ACS.

2000;

Epidemiology, prevention, and early detection of breast cancer.

Alberg AJ, Helzlsouer KJ.

Curr Opin Oncol. 1997 Nov; 9(6):505-11.

Breast cancer is a leading women's health issue. Continued advances in understanding the temporal sequencing of relevant exposures promises to shed light on the continuum of breast carcinogenesis. Oral contraceptive use and the transient increase in risk following childbirth are exposures that affect the near-term risk of breast cancer. The availability of commercial testing for inherited susceptibility to breast cancer has accelerated the need for data to develop sound policy for implementing gene testing. The risks associated with BRCA1 and BRCA2 mutations may be less than previously estimated. Antiestrogens with lesser risks than tamoxifen hold promise for chemoprevention, but await testing. Not enough is known to formulate primary prevention strategies based on lifestyle interventions. Further understanding lifestyle factors that may be involved in the etiology of breast cancer and are amenable to preventive intervention thus remains a top priority, with diet and physical activity of greatest interest

Curcumin is an in vivo inhibitor of angiogenesis.

Arbiser JL, Klauber N, Rohan R, et al.

Mol Med. 1998 Jun; 4(6):376-83.

BACKGROUND: Curcumin is a small-molecular-weight compound that is isolated from the commonly used spice turmeric. In animal models, curcumin and its derivatives have been shown to inhibit the progression of chemically induced colon and skin cancers. The genetic changes in carcinogenesis in these organs involve different genes, but curcumin is effective in preventing carcinogenesis in both organs. A possible explanation for this finding is that curcumin may inhibit angiogenesis. MATERIALS AND METHODS: Curcumin was tested for its ability to inhibit the proliferation of primary endothelial cells in the presence and absence of basic fibroblast growth factor (bFGF), as well as its ability to inhibit proliferation of an immortalized endothelial cell line. Curcumin and its derivatives were subsequently tested for their ability to inhibit bFGF-induced corneal neovascularization in the mouse cornea. Finally, curcumin was tested for its ability to inhibit phorbol ester-stimulated vascular endothelial growth factor (VEGF) mRNA production. RESULTS: Curcumin effectively inhibited endothelial cell proliferation in a dose-dependent manner. Curcumin and its derivatives demonstrated significant inhibition of bFGF-mediated corneal neovascularization in the mouse. Curcumin had no effect on phorbol ester-stimulated VEGF production. CONCLUSIONS: These results indicate that curcumin has direct antiangiogenic activity in vitro and in vivo. The activity of curcumin in inhibiting carcinogenesis in diverse organs such as the skin and colon may be mediated in part through angiogenesis inhibition

Long-chain n-3-to-n-6 polyunsaturated fatty acid ratios in breast adipose tissue from women with and without breast cancer.

Bagga D, Anders KH, Wang HJ, et al.

Nutr Cancer. 2002; 42(2):180-5.

Animal studies suggest that dietary polyunsaturated fatty acids (PUFAs) of the n-6 class, found in corn and safflower oils, may be precursors of intermediates involved in the development of mammary tumors, whereas long-chain (LC) n-3 PUFAs, found in fish oil, can inhibit these effects. This case-control study was designed to examine the relationship between the PUFA composition of breast adipose tissue and the risk of breast cancer. Using fatty acid levels in breast adipose tissue as a biomarker of past qualitative dietary intake of fatty acids, we examined the hypothesis that breast cancer risk is negatively associated with specific LC n-3 PUFAs (eicosapentaenoic acid and docosahexaenoic acid) and positively associated with n-6 PUFAs (linoleic acid and arachidonic acid). Breast adipose tissue was collected from 73 breast cancer patients and 74 controls with macromastia. The fatty acid levels were determined by gas-liquid chromatography. A logistic regression model was used to obtain odds ratio estimates while adjusting for age. The age-adjusted n-6 PUFA (linoleic acid and arachidonic acid) content was significantly higher in cases than in controls (P = 0.02). There was a trend in the age-adjusted data suggesting that, at a given level of n-6 PUFA, LC n-3 PUFAs (eicosapentaenoic acid and docosahexaenoic acid) may have a protective effect (P = 0.06). A similar inverse relationship was observed with LC n-3-to-n-6 ratio when the data were adjusted for age (P = 0.09). We conclude that total n-6 PUFAs may be contributing to the high risk of breast cancer in the United States and that LC n-3 PUFAs, derived from fish oils, may have a protective effect

Sentinel node biopsy in breast cancer.

Barnwell JM, Arredondo MA, Kollmorgen D, et al.

Ann Surg Oncol. 1998 Mar; 5(2):126-30.

BACKGROUND: Sentinel lymph node biopsy (SNB) in breast cancer may be used in place of axillary lymph node dissection (ALND) if SNB accurately stages the axilla. This study assessed the success and accuracy of axillary SNB with isosulfan blue (ISB) and technetium-99 sulfur colloid (TSC) compared to ALND. METHODS: Forty-two women with T1 or T2 breast cancer underwent SNB and ALND. Sixty to 90 minutes before anesthetic induction, a mixture of 3 mL ISB and 1 mCi TSC was injected around the primary cancer or prior biopsy site. Intraoperatively, the SLN was identified using a gamma detector (Neoprobe 1000) or by visualization of the blue-stained lymph node and afferent lymphatics. The SLN was excised separately, and a level I/II ALND was completed. The histologic findings of the axillary contents and SLN were compared. RESULTS: An axillary SLN was found in 38 of 42 (90%) cases. SLN localization rate and predictive value were the same for women who had and those who had not undergone excisional biopsy before the date of SNB. Fifteen of 42 (36%) patients had lymph node metastases. The SLN was positive in all women with axillary metastases (negative predictive value, 100%). CONCLUSIONS: If confirmed by larger series, a negative SNB may eliminate the need for ALND for select women with breast cancer

Prospective evaluation of vitamin E for hot flashes in breast cancer survivors.

Barton DL, Loprinzi CL, Quella SK, et al.

J Clin Oncol. 1998 Feb; 16(2):495-500.

PURPOSE: Hot flashes represent a substantial clinical problem for some breast cancer survivors. Although estrogen or progesterone preparations can alleviate these symptoms in many patients, concern remains regarding the use of hormonal preparations in such women. Thus, there is a perceived need for nonhormonal treatments for hot flashes for breast cancer survivors. Based on anecdotal evidence that vitamin E was helpful, we designed a trial to investigate this matter. METHODS: We developed and conducted a placebo-controlled, randomized, crossover trial where, after a 1 week baseline period, patients received 4 weeks of vitamin E 800 IU daily, then 4 weeks of an identical-appearing placebo, or vice versa. Diaries were used to measure potential toxicities and hot flashes during the baseline week and the two subsequent 4-week treatment periods. RESULTS: The 120 patients evaluated for toxicity failed to show any. The 105 patients who finished the first treatment period showed a similar reduction in hot flash frequencies (25% v 22%; P = .90) for the two study arms. A crossover analysis, however, showed that vitamin E was associated with a minimal decrease in hot flashes (one less hot flash per day than was seen with a placebo) (P < or = ".05)." At the study end, patients did not prefer vitamin E over the placebo (32% v 29%, respectively). CONCLUSION: Although this trial was able to show a statistically significant hot flash reduction with vitamin E compared to a placebo, the clinical magnitude of this reduction was marginal

Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses.

Baum M, Buzdar A, Cuzick J, et al.

Cancer. 2003 Nov 1; 98(9):1802-10.

BACKGROUND: The first analysis of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial (median follow-up, 33 months) demonstrated that in adjuvant endocrine therapy for postmenopausal patients with early-stage breast cancer, anastrozole was superior to tamoxifen in terms of disease-free survival (DFS), time to recurrence (TTR), and incidence of contralateral breast cancer (CLBC). In the current article, the results of the first efficacy update, based on a median follow-up period of 47 months, are reported along with the results of an updated safety analysis, performed 7 months after the first analysis (median duration of treatment, 36.9 months). METHODS: DFS, TTR, CLBC incidence, and safety were assessed in the same patient group as in the first analysis of the ATAC trial. RESULTS: DFS estimates at 4 years remained significantly more favorable (86.9% vs. 84.5%, respectively) for patients receiving anastrozole compared with those receiving tamoxifen (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.76-0.99; P = 0.03). The benefit generated by anastrozole in terms of DFS was even greater in patients with hormone receptor-positive tumors (HR, 0.82; 95% CI, 0.70-0.96; P = 0.014). The HR for TTR also indicated a significant benefit for patients receiving anastrozole compared with those receiving tamoxifen (HR, 0.83; 95% CI, 0.71-0.96; P = 0.015), with additional benefit for patients with hormone receptor-positive tumors (HR, 0.78; 95% CI, 0.65-0.93; P = 0.007). CLBC incidence data also continued to favor anastrozole (odds ratio [OR], 0.62; 95% CI, 0.38-1.02; P = 0.062), and statistical significance was achieved in the hormone receptor-positive subgroup (OR, 0.56; 95% CI, 0.32-0.98; P = 0.042). The updated safety analysis also confirmed the findings of the first analysis, in that endometrial cancer (P = 0.007), vaginal bleeding and discharge (P < 0.001 for both), cerebrovascular events (P < 0.001), venous thromboembolic events (P < 0.001), and hot flashes (P < 0.001) all occurred less frequently in the anastrozole group, whereas musculoskeletal disorders and fractures (P < 0.001 for both) continued to occur less frequently in the tamoxifen group. These results indicated that the safety profile of anastrozole remained consistent. CONCLUSIONS: After an additional follow-up period, anastrozole continues to show superior efficacy, which is most apparent in the clinically relevant hormone receptor-positive population. Furthermore, anastrozole has numerous noteworthy advantages in terms of tolerability compared with tamoxifen. These findings suggest that the benefits of anastrozole are likely to be maintained in the long term and provide further support for the status of anastrozole as a valid treatment option for postmenopausal women with hormone-sensitive early-stage breast cancer

The dietary pigment curcumin reduces endothelial tissue factor gene expression by inhibiting binding of AP-1 to the DNA and activation of NF-kappa B.

Bierhaus A, Zhang Y, Quehenberger P, et al.

Thromb Haemost. 1997 Apr; 77(4):772-82.

The natural occurring pigment curcumin, a major component of the spice tumeric, has been described to have antioxidative, anti-tumorpromoting, anti-thrombotic and anti-inflammatory properties. It appears, that the pleiotropic effects of curcumin are at least partly due to inhibition of the transcription factors NF-kappa B and AP-1. This study investigates the effect of curcumin on the TNF alpha induced expression of endothelial Tissue Factor (TF), the central mediator of coagulation known to be controlled by AP-1 and NF-kappa B. When bovine aortic endothelial cells (BAEC) were preincubated in the presence of curcumin, TNF alpha induced TF gene transcription and expression were reduced. Transient transfection studies with TF-promoter plasmids revealed that both, NF-kappa B and AP-1 dependent TF expression, were reduced by curcumin action. The observed inhibitions were due to distinct mechanisms. Curcumin inhibited TNF alpha induced I kappa B alpha degradation and the nuclear import of NF-kappa B. In contrast, inhibition of AP-1 was due to a direct interaction of curcumin with AP-1-binding to its DNA binding motif. Thus, curcumin inhibits NF-kappa B and AP-1 by two different mechanisms and reduces expression of endothelial genes controlled by both transcription factors in vitro

Indole derivatives useful to treat estrogen-related neoplasms and disorders.

Bitonti AJ MISFWJJEWP.

1999(5,877,202)

Melatonin as a chronobiotic/anticancer agent: cellular, biochemical, and molecular mechanisms of action and their implications for circadian-based cancer therapy.

Blask DE, Sauer LA, Dauchy RT.

Curr Top Med Chem. 2002 Feb; 2(2):113-32.

Melatonin, as a new member of an expanding group of regulatory factors that control cell proliferation and loss, is the only known chronobiotic, hormonal regulator of neoplastic cell growth. At physiological circulating concentrations, this indoleamine is cytostatic and inhibits cancer cell proliferation in vitro via specific cell cycle effects. At pharmacological concentrations, melatonin exhibits cytotoxic activity in cancer cells. At both physiological and pharmacological concentrations, melatonin acts as a differentiating agent in some cancer cells and lowers their invasive and metastatic status through alterations in adhesion molecules and maintenance of gap junctional intercellular communication. In other cancer cell types, melatonin, either alone or in combination with other agents, induces apoptotic cell death. Biochemical and molecular mechanisms of melatonin's oncostatic action may include regulation of estrogen receptor expression and transactivation, calcium/calmodulin activity, protein kinase C activity, cytoskeletal architecture and function, intracellular redox status, melatonin receptor-mediated signal transduction cascades, and fatty acid transport and metabolism. A major mechanism mediating melatonin's circadian stage-dependent tumor growth inhibitory action is the suppression of epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase (MAPK) activity. This occurs via melatonin receptor-mediated blockade of tumor linoleic acid uptake and its conversion to 13-hydroxyoctadecadienoic acid (13-HODE) which normally activates EGFR/MAPK mitogenic signaling. This represents a potentially unifying model for the chronobiological inhibitory regulation of cancer growth by melatonin in the maintenance of the host/cancer balance. It also provides the first biological explanation of melatonin-induced enhancement of the efficacy and reduced toxicity of chemo- and radiotherapy in cancer patients

Coenzymes Q: stimulants of the phagocytic activity in rats and immune response in mice.

Bliznakov E, Casey A, Premuzic E.

Experientia. 1970 Sep 26; 26(9):953-4.

Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence.

Block G, Patterson B, Subar A.

Nutr Cancer. 1992; 18(1):1-29.

Approximately 200 studies that examined the relationship between fruit and vegetable intake and cancers of the lung, colon, breast, cervix, esophagus, oral cavity, stomach, bladder, pancreas, and ovary are reviewed. A statistically significant protective effect of fruit and vegetable consumption was found in 128 of 156 dietary studies in which results were expressed in terms of relative risk. For most cancer sites, persons with low fruit and vegetable intake (at least the lower one-fourth of the population) experience about twice the risk of cancer compared with those with high intake, even after control for potentially confounding factors. For lung cancer, significant protection was found in 24 of 25 studies after control for smoking in most instances. Fruits, in particular, were significantly protective in cancers of the esophagus, oral cavity, and larynx, for which 28 of 29 studies were significant. Strong evidence of a protective effect of fruit and vegetable consumption was seen in cancers of the pancreas and stomach (26 of 30 studies), as well as in colorectal and bladder cancers (23 of 38 studies). For cancers of the cervix, ovary, and endometrium, a significant protective effect was shown in 11 of 13 studies, and for breast cancer a protective effect was found to be strong and consistent in a meta analysis. It would appear that major public health benefits could be achieved by substantially increasing consumption of these foods

Insulin and cancer.

Boyd DB.

Integr Cancer Ther. 2003 Dec; 2(4):315-29.

Obesity has recently been linked to mortality from the majority of cancers. The insulin/insulin-like growth factor (IGF) system may partly explain this effect. The metabolic syndrome, associated with hyperinsulinemia, may modulate this effect. Recent evidence supports the role of insulin and IGF-1 as important growth factors, acting through the tyrosine kinase growth factor cascade in enhancing tumor cell proliferation. In addition, the metabolic syndrome associated with a chronic inflammatory state and accompanying cytokine abnormalities may also contribute to tumor progression. Growing links between insulin and the etiology as well as prognosis in colon, prostate, pancreatic, and, particularly, breast cancer are reviewed. Of particular concern is the evidence that elevated IGF-1 may interfere with cancer therapy, adversely affecting prognosis. The role of insulin is of concern because of the increasing levels of obesity and the associated metabolic syndrome. Weight gain, through typical Western diet; limited levels of activity; and, more recently, stress-related changes in neuroendocrine function may lead to insulin resistance and hyperinsulinemia. The opportunity for a multidisciplinary approach involving nutrition, exercise, and stress reduction in an integrative setting may be crucial to limiting the insulin-resistant state and improving cancer outcomes

Effects of dietary indole-3-carbinol on estradiol metabolism and spontaneous mammary tumors in mice.

Bradlow HL, Michnovicz J, Telang NT, et al.

Carcinogenesis. 1991 Sep; 12(9):1571-4.

Indole-3-carbinol (I3C) is a potent inducer of cytochrome P450 enzymes in many species, including humans. We therefore studied alterations in the cytochrome P450-dependent metabolism of estradiol in different strains of mice consuming I3C in semisynthetic powdered diets at doses ranging from 250 to 5000 p.p.m. (34-700 mg/kg/day) for different periods of time. In short-term metabolic studies (3 weeks), wet liver weight increased in SW and C3H/OuJ mice in a dose-responsive manner. Dietary I3C increased the cytochrome P450 content measured in hepatic microsomes, as well as the extent of estradiol 2-hydroxylation, up to 5-fold. In a long-term feeding experiment (8 months), female C3H/OuJ mice consumed synthetic diets containing I3C at 0, 500 or 2000 p.p.m. Mammary tumor incidence and multiplicity were significantly lower at both doses of I3C, and tumor latency was prolonged in the high-dose group. We conclude that I3C is an inducer of hepatic P450-dependent estrogen metabolism in mice, and that it is chemopreventive in the C3H/OuJ mouse mammary tumor model. This protective effect may be mediated in part by the increased 2-hydroxylation and consequent inactivation of endogenous estrogens

A new indole-3-carbinol tetrameric derivative inhibits cyclin-dependent kinase 6 expression, and induces G1 cell cycle arrest in both estrogen-dependent and estrogen-independent breast cancer cell lines.

Brandi G, Paiardini M, Cervasi B, et al.

Cancer Res. 2003 Jul 15; 63(14):4028-36.

Indole-3-carbinol (I3C), autolysis product of glucosinolates present in cruciferous vegetables, has been indicated as a promising agent in preventing the development and progression of breast cancer. I3C has been shown to inhibit the growth of human cancer cells in vitro and possesses anticarcinogenic activity in vivo. Because I3C is unstable and may be converted into many polymeric products in the digestive tract, it is not yet clear whether the biological activity observed can be attributed to I3C or some of its polymeric products. In this study we synthesized a stable I3C cyclic tetrameric derivative and investigated its effects on a panel of human breast cancer cell lines. The I3C tetramer suppressed the growth of both estrogen receptor (ER) -positive (MCF-7, 734B, and BT474) and ER-negative (BT20, MDA-MB-231, and BT539) human breast cancer cell lines, and it was found to induce G(1) cell cycle arrest in a dose-dependent manner without evidence of apoptosis, suggesting a growth arrest via a cytostatic mechanism. At the molecular level, the tetramer inhibited cyclin-dependent kinase (CDK) 6 expression and activity, induced an increase in the level of p27(kip1), and reduced the level of retinoblastoma protein expression. Contrarily to CDK6, the level of CDK4, the other kinase involved in the G(1) phase of the cell cycle, remains unchanged. Interestingly, the tetramer resulted about five times more active than I3C in suppressing the growth of human breast cancer cells. On the whole, our data suggest that the I3C tetrameric derivative is a novel lead inhibitor of breast cancer cell growth that may be a considered a new, promising therapeutic agent for both ER+ and ER- breast cancer

Melatonin in humans.

Brzezinski A.

N Engl J Med. 1997 Jan 16; 336(3):186-95.

High dietary level of synthetic vitamin E on lipid peroxidation, membrane fatty acid composition and cytotoxicity in breast cancer xenograft and in mouse host tissue.

Cameron IL, Munoz J, Barnes CJ, et al.

Cancer Cell Int. 2003 Mar 12; 3(1):3.

BACKGROUND: d-alpha-tocopherol is a naturally occurring form of vitamin E not previously known to have antitumor activity. Synthetic vitamin E (sE) is a commonly used dietary supplement consisting of a mixture of d-alpha-tocopherol and 7 equimolar stereoisomers. To test for antilipid peroxidation and for antitumor activity of sE supplementation, two groups of nude mice bearing a MDA-MB 231 human breast cancer tumor were fed an AIN-76 diet, one with and one without an additional 2000 IU/kg dry food (equivalent to 900 mg of all-rac-alpha-tocopherol or sE). This provided an intake of about 200 mg/kg body weight per day. The mice were killed at either 2 or 6 weeks after the start of dietary intervention. During necropsy, tumor and host tissues were excised for histology and for biochemical analyses. RESULTS: Tumor growth was significantly reduced by 6 weeks of sE supplementation. Thiobarbituric acid reactive substances, an indicator of lipid peroxidation, were suppressed in tumor and in host tissues in sE supplemented mice. In the sE treated mice, the fatty acid composition of microsomal and mitochondrial membranes of tumor and host tissues had proportionately less linoleic acid (n-6 C 18-2), similar levels of arachidonic acid (n-6 C 20-4), but more docosahexanoic acid (n-3 C 22-6). The sE supplementation had no significant effect on blood counts or on intestinal histology but gave some evidence of cardiac toxicity as judged by myocyte vacuoles and by an indicator of oxidative stress (increased ratio of Mn SOD mRNA over GPX1 mRNA). CONCLUSIONS: At least one of the stereoisomers in sE has antitumor activity. Synthetic vitamin E appears to preferentially stabilize membrane fatty acids with more double bonds in the acyl chain. Although sE suppressed tumor growth and lipid peroxidation, it may have side-effects in the heart

Relation of tumor size, lymph node status, and survival in 24,740 breast cancer cases.

Carter CL, Allen C, Henson DE.

Cancer. 1989 Jan 1; 63(1):181-7.

Two of the most important prognostic indicators for breast cancer are tumor size and extent of axillary lymph node involvement. Data on 24,740 cases recorded in the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute were used to evaluate the breast cancer survival experience in a representative sample of women from the United States. Actuarial (life table) methods were used to investigate the 5-year relative survival rates in cases with known operative/pathologic axillary lymph node status and primary tumor diameter. Survival rates varied from 45.5% for tumor diameters equal to or greater than 5 cm with positive axillary nodes to 96.3% for tumors less than 2 cm and with no involved nodes. The relation between tumor size and lymph node status was investigated in detail. Tumor diameter and lymph node status were found to act as independent but additive prognostic indicators. As tumor size increased, survival decreased regardless of lymph node status; and as lymph node involvement increased, survival status also decreased regardless of tumor size. A linear relation was found between tumor diameter and the percent of cases with positive lymph node involvement. The results of our analyses suggest that disease progression to distant sites does not occur exclusively via the axillary lymph nodes, but rather that lymph node status serves as an indicator of the tumor's ability to spread

Conjugated linoleic acid content in breast adipose tissue of breast cancer patients and the risk of metastasis.

Chajes V, Lavillonniere F, Maillard V, et al.

Nutr Cancer. 2003; 45(1):17-23.

The association between the level of conjugated linoleic acid (CLA) in breast adipose tissue at the time of diagnosis and the subsequent development of metastasis was examined in a cohort of 209 patients presenting with an initially localized breast cancer. CLA level in breast adipose tissue was used as a qualitative biomarker of its past dietary intake. Biopsies of adipose tissue were obtained at the time of initial surgery. A CLA-enriched fraction was prepared by high performance liquid chromatography and CLA measured as a percentage of total fatty acids, using capillary gas chromatography. Mean CLA level was low (0.44% of total fatty acids) and the range between patients was narrow (0.19-0.85). With a median follow-up time of 7.5 yr, 45 patients developed metastases. A Cox proportional hazard regression model was used to identify prognostic factors. We did not find any significant association between CLA level in adipose fat and either the prognostic factor (tumor size, nodal status, histoprognostic grade, mitotic index, and estrogen or progesterone receptors) or the risk of metastasis or death. We concluded that CLA are unlikely to be involved in survivorship. However, the hypothesis that a higher intake of CLA might have a protective effect on the risk of metastasis cannot be ruled out from these data, since the level of CLA in breast cancer patients' adipose tissue is likely to be too low and the range of CLA distribution too narrow for any protection to be detectable

Indole-3-carbinol and diindolylmethane as aryl hydrocarbon (Ah) receptor agonists and antagonists in T47D human breast cancer cells.

Chen I, Safe S, Bjeldanes L.

Biochem Pharmacol. 1996 Apr 26; 51(8):1069-76.

Indole-3-carbinol (I3C) is a major component of Brassica vegetables, and diindolylmethane (DIM) is the major acid-catalyzed condensation product derived from I3C. Both compounds competitively bind to the aryl hydrocarbon (Ah) receptor with relatively low affinity. In Ah-responsive T47D human breast cancer cells, I3C and DIM did not induce significantly CYP1A1-dependent ethoxyresorufin O-deethylase (EROD) activity or CYP1A1 mRNA levels at concentrations as high as 125 or 31 microM, respectively. A 1 nM concentration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced EROD activity in these cells, and cotreatment with TCDD plus different concentrations of I3C (1-125 microM) or DIM (1-31 microM) resulted in a > 90% decrease in the induced response at the highest concentration of I3C or DIM. I3C or DIM also partially inhibited (< 50%) induction of CYP1A1 mRNA levels by TCDD and reporter gene activity, using an Ah-responsive plasmid construct in transient transfection assays. In T47D cells cotreated with 5 nM [3H]TCDD alone or in combination with 250 microM I3C or 31 microM DIM, there was a 37 and 73% decrease, respectively, in formation of the nuclear Ah receptor. The more effective inhibition of induced EROD activity by I3C and DIM was due to in vitro inhibition of enzyme activity. Thus, both I3C and DIM are partial Ah receptor antagonists in the T47D human breast cancer cell line

Dietary flaxseed inhibits human breast cancer growth and metastasis and downregulates expression of insulin-like growth factor and epidermal growth factor receptor.

Chen J, Stavro PM, Thompson LU.

Nutr Cancer. 2002; 43(2):187-92.

Recent studies indicate that diets rich in phytoestrogens and n-3 fatty acid have anticancer potential. This study determined the effect of flaxseed (FS), the richest source of lignans and alpha-linolenic acid, on growth and metastasis of established human breast cancer in a nude mice model. Estrogen receptor-negative human breast cancer cells, MDA-MB-435, were injected into the mammary fat pad of mice (Ncr nu/nu) fed a basal diet (BD). At Week 8, mice were randomized into two diet groups, such that the groups had similar tumor size and body weight. One continued on the BD, while the other was changed to BD supplemented with 10% FS, until sacrifice at Week 15. A significant reduction (P < 0.05) in tumor growth rate and a 45% reduction (P = "0.08)" in total incidence of metastasis were observed in the FS group. Lung metastasis incidence was 55.6% in the BD group and 22.2% in the FS group, while the lymph node metastasis incidence was 88.9% in the BD group and 33.3% in the FS group (P < 0.05). Mean tumor number (tumor load) of total and lymph node metastasis was significantly lower in the FS than in the BD group (P < 0.05). Metastatic lung tumor number was reduced by 82%, and a significantly lower tumor trend (P < 0.01) was observed in the FS group. Lung weight, which also reflects metastatic tumor load, in the FS group was reduced by 20% (P < 0.05) compared with the BD group. Immunohistochemical study showed that Ki-67 labeling index and expression of insulin-like growth factor I and epithelial growth factor receptor in the primary tumor were lower in the FS (P < 0.05) than in the BD group. In conclusion, flaxseed inhibited the established human breast cancer growth and metastasis in a nude mice model, and this effect is partly due to its downregulation of insulin-like growth factor I and epidermal growth factor receptor expression

Prevention by coenzyme Q10 of the electrocardiographic changes induced by adriamycin in rats.

Choe JY, Combs AB, Folkers K.

Res Commun Chem Pathol Pharmacol. 1979 Jan; 23(1):199-202.

The administration of adriamycin (ADM) to rats has consistently caused a widening of the QRS complex of the electrocardiogram. When coenzyme Q10 was also administered, beginning two days before ADM, this widening of the QRS complex and the elongation of the Q-T interval were reduced or totally prevented, depending upon conditions. ADM alone or with coenzyme Q10 did not alter the P-R interval. Some control by coenzyme Q10 of the cardiotoxicity of adriamycin in cancer patients is promising

Effect of conjugated linoleic acid isomers on growth factor-induced proliferation of human breast cancer cells.

Chujo H, Yamasaki M, Nou S, et al.

Cancer Lett. 2003 Dec 8; 202(1):81-7.

We evaluated the effect of conjugated linoleic acid (CLA) isomers on the growth factor-induced proliferation of human breast cancer MCF-7 cells. When MCF-7 cells were cultured in RPMI 1640 medium supplemented with 1% fetal bovine serum (FBS), CLA inhibited the proliferation and notably cis9, trans11 (c9,t11)-CLA showed the strongest effect. However, cells barely grew when cultured with 1% charcoal-treated FBS (cFBS). Proliferation was promoted in cFBS cultured cells by the addition of 17beta-estradiol (E2), insulin, and epidermal growth factor (EGF). Trans10, cis12 (T10,c12)-CLA inhibited cell proliferation induced by E2 and insulin, but not by EGF. T10,c12-CLA also exhibited cell-killing activity when cells were induced with insulin. On the other hand, c9,t11-CLA was shown to have no effect on MCF-7 cell proliferation induced by and of these three growth factors. In conclusion, although both c9, t11 and t10, c12-CLA can inhibit the proliferation of MCF-7 cells, our results suggested that they have separate mechanisms and different targets of actions

Epidemiology of breast cancer. Findings from the nurses' health study.

Colditz GA.

Cancer. 1993 Feb 15; 71(4 Suppl):1480-9.

BACKGROUND. The epidemiology of breast cancer was reviewed in the context of hormonal, hereditary, histologic, and dietary risk factors. METHODS. Literature review. RESULTS. Late age at menarche and early age at first birth decrease the risk of breast cancer as does an early age at menopause. These risk factors relate to the lifetime exposure of the breast tissue to ovarian hormones. Although an early first birth is associated with a transient increase in the risk of breast cancer, perhaps as a result of the breast's exposure to high levels of hormones before terminal differentiation, in older women, parity is associated with a decreased risk of breast cancer. Among postmenopausal women, obesity is associated with higher levels of estrogens and an increased risk of breast cancer. Within the strata of breast cancer stages at diagnosis, obesity is associated with increased mortality, again supporting the influence of endogenous estrogens on this disease's incidence, recurrence, and survival rates. Consistent with these relationships, current use of estrogen therapy among postmenopausal women is associated with an increased risk of breast cancer. A family history of breast cancer is associated with approximately a two-fold increase in the risk of breast cancer, and this risk is greater if the diagnosis was made when the woman's mother was young, although even a diagnosis in an older mother is associated with an increased risk in her daughters. The follow-up of women with a history of benign breast biopsy results shows that atypical hyperplasia is associated with a fourfold increase in risk compared with a biopsy specimen without proliferative changes. Atypia doubles the risk. These data support the concept of atypia as a precursor lesion for breast cancer and may warrant its use as a marker in further studies. Consistent data from retrospective and prospective studies show a positive association between moderate alcohol intake and the risk of breast cancer. This may reflect the increase in estrogen levels observed among women who consume alcohol. Data from prospective studies do not support a relationship between dietary fat intake and the risk of breast cancer either in premenopausal or postmenopausal women. CONCLUSIONS. Few of these associations offer the potential for intervention to reduce the breast cancer risk

Reduction by coenzyme Q10 of the acute toxicity of adriamycin in mice.

Combs AB, Choe JY, Truong DH, et al.

Res Commun Chem Pathol Pharmacol. 1977 Nov; 18(3):565-8.

Pretreatment for four days with coenzyme Q10 (COQ10) reduced the acute toxicity in mice treated with adriamycin. In two sequential protocols, adriamycin allowed only 36 and 42% survival, respectively. Pretreatment with COQ10 allowed 80 and 86% survival, respectively. The differences are significant, p less than 0.05. The mechanism for this reduction in the acute toxicity may be based upon the prevention by the supplementary COQ10 of the inhibition caused by adriamycin to COQ10-dependent enzymes in cardiac and and other tissues. The prospect of diminishing the toxicity of adriamycin in cancer patients remains promising and important

Influence of melatonin on invasive and metastatic properties of MCF-7 human breast cancer cells.

Cos S, Fernandez R, Guezmes A, et al.

Cancer Res. 1998 Oct 1; 58(19):4383-90.

Melatonin, the principal pineal gland hormone, exerts a direct antiproliferative effect on estrogen-responsive MCF-7 cells in culture. The purpose of the current study was to investigate the effects of melatonin on the invasion capacity of MCF-7 cells. In vitro, melatonin at physiological doses (1 nM) reduced (P < 0.001) the invasiveness of tumoral cells measured in Falcon invasion chambers. Subphysiological (0.1 pM) and pharmacological concentrations (10 microM) of melatonin failed to inhibit cell invasion. Melatonin was also able to block 17beta-estradiol-induced invasion (P < 0.001). Pretreatment of MCF-7 cells with 1 nM melatonin increased the response of tumoral cells to the anti-invasive effects of this indolamine. To explore possible mechanisms by which melatonin reduces invasiveness, we measured the attachment of MCF-7 cells to a basement membrane, the chemotactic response of the cells, and their type IV collagenolytic activity. The presence of melatonin (1 nM) in the culture medium significantly reduced the ability of MCF-7 cells to attach to the basement membrane; this effect was enhanced by pretreating the cells with the same indolamine (P < 0.001). Melatonin also counteracts the stimulatory effects of 17beta-estradiol on cell adhesion (P < 0.001). The chemotactic response of MCF-7 cells also decreased in the presence of 1 nM melatonin, and this melatonin-induced reduction of cell migration was more effective on cells that were previously incubated for 5 days with melatonin than it was on nonpretreated cells (P < 0.001). The simultaneous addition of 17beta-estradiol and melatonin resulted in a significantly lower chemotactic response than that of 17beta-estradiol-treated cells (P < 0.001). However, type IV collagenolytic activity was not influenced by melatonin. Our results demonstrate that melatonin reduces the invasiveness of MCF-7 cells, causing a decrease in cell attachment and cell motility, probably by interacting with the estrogen-mediated mechanisms of MCF-7 cell invasiveness. In addition, we also studied the influence of melatonin on the expression of two cell surface adhesion molecules (E-cadherin and beta1 integrin) and an intermediate filament protein (vimentin), the expression of which has been correlated with the relative invasive capacity of human breast cancer cells. The culture of tumor cells in the presence of melatonin (1 nM) increased the membrane staining for E-cadherin and beta1 integrin as well as the number of E-cadherin and beta1 integrin immunoreactive cells (P < 0.01). Neither control MCF-7 cells nor those treated with melatonin stained for vimentin. Preliminary in vivo experiments carried out on ovariectomized athymic nude mice implanted with 17beta-estradiol pellets and inoculated with 5 x 10(6) MCF-7 cells in the inguinal mammary fat pad suggest that melatonin could decrease the tumorigenicity of these tumor cells. However, these results need further confirmation. Taken together, our results suggest that melatonin shifts MCF-7 human breast cancer cells to a lower invasive status by increasing the beta1 integrin subunit and E-cadherin expression and promoting the differentiation of tumor cells. Finally, our study points out the existence of the anti-invasive actions of melatonin as a part of the oncostatic action of melatonin

Influence of serum from healthy or breast tumor-bearing women on the growth of MCF-7 human breast cancer cells.

Cos S, Alvarez A, Mediavilla MD, et al.

Int J Mol Med. 2000 Jun; 5(6):651-6.

Sera from women healthy (HW) or with breast (BCW), ovarian or endometrial cancer, were added (10%) to the culture media of MCF-7 cells and cell proliferation assessed 4 days later to verify: a) whether sera from BCW, obtained before or 8 days after tumor ablaction, influence the proliferation of these cells, b) whether the effects of serum from BCW are specific for mammary tumor cells. Sera from BCW, but not sera from women with ovarian or endometrial cancer, increased MCF-7 cell proliferation in comparison with sera from HW. After surgical ablation of the breast tumors, serum's ability to increase MCF-7 cell proliferation decreased significantly. These effects cannot be explained by differences on serum levels of estradiol or melatonin. These results suggest the presence of growth-promoting substances of possible tumoral origin in serum of BCW, a fact that should be considered as support for the surgical treatment of tumor masses

Indole-3-carbinol inhibits the expression of cyclin-dependent kinase-6 and induces a G1 cell cycle arrest of human breast cancer cells independent of estrogen receptor signaling.

Cover CM, Hsieh SJ, Tran SH, et al.

J Biol Chem. 1998 Feb 13; 273(7):3838-47.

Indole-3-carbinol (I3C), a naturally occurring component of Brassica vegetables such as cabbage, broccoli, and Brussels sprouts, has been shown to reduce the incidence of spontaneous and carcinogen-induced mammary tumors. Treatment of cultured human MCF7 breast cancer cells with I3C reversibly suppresses the incorporation of [3H]thymidine without affecting cell viability or estrogen receptor (ER) responsiveness. Flow cytometry of propidium iodide-stained cells revealed that I3C induces a G1 cell cycle arrest. Concurrent with the I3C-induced growth inhibition, Northern blot and Western blot analyses demonstrated that I3C selectively abolished the expression of cyclin-dependent kinase 6 (CDK6) in a dose- and time-dependent manner. Furthermore, I3C inhibited the endogenous retinoblastoma protein phosphorylation and CDK6 phosphorylation of retinoblastoma in vitro to the same extent. After the MCF7 cells reached their maximal growth arrest, the levels of the p21 and p27 CDK inhibitors increased by 50%. The antiestrogen tamoxifen also suppressed MCF7 cell DNA synthesis but had no effect on CDK6 expression, while a combination of I3C and tamoxifen inhibited MCF7 cell growth more stringently than either agent alone. The I3C-mediated cell cycle arrest and repression of CDK6 production were also observed in estrogen receptor-deficient MDA-MB-231 human breast cancer cells, which demonstrates that this indole can suppress the growth of mammary tumor cells independent of estrogen receptor signaling. Thus, our observations have uncovered a previously undefined antiproliferative pathway for I3C that implicates CDK6 as a target for cell cycle control in human breast cancer cells. Moreover, our results establish for the first time that CDK6 gene expression can be inhibited in response to an extracellular antiproliferative signal

Indole-3-carbinol and tamoxifen cooperate to arrest the cell cycle of MCF-7 human breast cancer cells.

Cover CM, Hsieh SJ, Cram EJ, et al.

Cancer Res. 1999 Mar 15; 59(6):1244-51.

The current options for treating breast cancer are limited to excision surgery, general chemotherapy, radiation therapy, and, in a minority of breast cancers that rely on estrogen for their growth, antiestrogen therapy. The naturally occurring chemical indole-3-carbinol (I3C), found in vegetables of the Brassica genus, is a promising anticancer agent that we have shown previously to induce a G1 cell cycle arrest of human breast cancer cell lines, independent of estrogen receptor signaling. Combinations of I3C and the antiestrogen tamoxifen cooperate to inhibit the growth of the estrogen-dependent human MCF-7 breast cancer cell line more effectively than either agent alone. This more stringent growth arrest was demonstrated by a decrease in adherent and anchorage-independent growth, reduced DNA synthesis, and a shift into the G1 phase of the cell cycle. A combination of I3C and tamoxifen also caused a more pronounced decrease in cyclin-dependent kinase (CDK) 2-specific enzymatic activity than either compound alone but had no effect on CDK2 protein expression. Importantly, treatment with I3C and tamoxifen ablated expression of the phosphorylated retinoblastoma protein (Rb), an endogenous substrate for the G1 CDKs, whereas either agent alone only partially inhibited endogenous Rb phosphorylation. Several lines of evidence suggest that I3C works through a mechanism distinct from tamoxifen. I3C failed to compete with estrogen for estrogen receptor binding, and it specifically down-regulated the expression of CDK6. These results demonstrate that I3C and tamoxifen work through different signal transduction pathways to suppress the growth of human breast cancer cells and may, therefore, represent a potential combinatorial therapy for estrogen-responsive breast cancer

Bisphosphonates in the Management of Breast Cancer.

Cristofanilli M, Hortobagyi GN.

Cancer Control. 1999 May; 6(3):241-6.

BACKGROUND: Bone is the most frequent site of metastasis in patients with breast cancer. Bone metastasis, particularly osteolytic bone destruction, is usually associated with significant morbidity and deterioration of quality of life. Bisphosphonates are specific inhibitors of osteoclast activity used in the treatment of hypercalcemia of malignancy and osteolytic bone disease. METHODS: We reviewed pertinent literature on the use of bisphosphonates therapy to treat metastatic breast cancer. RESULTS: The use of bisphosphonates in the management of osteolytic bone metastases results in improved palliation of symptoms. Use of these agents in the adjuvant setting may help to prevent bone metastases. CONCLUSIONS: Bisphosphonates represent an effective palliative treatment when combined with chemotherapy and hormonal therapy for the management of osteolytic bone metastases. Identifying the exact mechanism of action requires further investigation to better define the possibility of a direct antitumor effect. The role of bisphosphonates in the adjuvant setting is still controversial, pending the results of large randomized trials

In Disease of the Breast.

Davidson NE, Kennedy MJADKDc.

2000; Second Edition

Protein kinase C and breast cancer.

Davidson NE, Kennedy MJ.

Cancer Treat Res. 1996; 83:91-105.

Bisphosphonates in the treatment of bone diseases.

Delmas PD.

N Engl J Med. 1996 Dec 12; 335(24):1836-7.

Effects of indole-3-carbinol (I3C) and phenethyl isothiocyanate (PEITC) on 7,12-dimethylbenz[a]anthracene (DMBA)-induced DNA adducts in rat mammary glands and liver (meeting abstract).

Devanaboyina U.

Proc Annu Meet Am Assoc Cancer Res. 1997;(38):2427.

Sensitive detection of 8-hydroxy-2'deoxyguanosine in DNA by 32P-postlabeling assay and the basal levels in rat tissues.

Devanaboyina U, Gupta RC.

Carcinogenesis. 1996 May; 17(5):917-24.

Oxidative damage from reactive oxygen species including free radicals has been considered to play a vital role in many degenerative diseases and measurement of 8-hydroxy-2'-deoxyguanosine (Oh8dG) in tissue DNA has been used as a benchmark for oxidative DNA damage. We report here an ultrasensitive 32P-postlabeling method to detect and quantitate Oh8dG in DNA and have determined basal levels of Oh8dG in rat tissues. The method is comprised of DNA digestion to 3'-monophosphates, 5'-32P-labeling, conversion to 5'-monophosphates and separation by a 2-directional PEI-cellulose TLC (D1 = 1.5 M formic acid; and D2 = 0.6 M ammonium formate, pH 6.0). Under these conditions, all radioactive contaminants were either removed from the chromatogram (normal nucleotides and 32Pi) or remained at the origin (ATP and other contaminants), while Oh8dG migrated in the middle of the chromatogram. Calf thymus DNA incubated with ascorbic acid and H202 produced predominantly one spot under the chromatography conditions used; a chromatographically identical spot was also detected in untreated DNA, but at a much lower level (125 +/- 40 Oh8dG/10(6) nucleotides). A chromatographically identical spot was also found in dGp incubated with ascorbic acid and H202, but not with dAp, dCp or dTp. When applied to rat tissue DNA, the assay readily permitted detection of Oh8dG in the liver, lung, kidney, heart, brain, spleen, intestines and mammary epithelial cells of 3-month old female Sprague-Dawley rats. The tissue Oh8dG levels were found in the range of 87 +/- 29 to 133 +/- 49 per 10(6) nucleotides, with liver and heart being the highest and kidney and brain the lowest. These values are in the vicinity to those found by gas chromatography/mass spectrometry but 10-50 times higher than those reported by HPLC-electrochemical detection. Because of its high sensitivity (<1 Oh8dG per 10(5-6) nucleotides) to detect Oh8dG using nanogram quantity of DNA digest, the 32P-postlabeling method is likely to be valuable in quantitating Oh8dG in human tissue biopsies

Conjugated linoleic acid and oxidative behaviour in cancer cells.

Devery R, Miller A, Stanton C.

Biochem Soc Trans. 2001 May; 29(Pt 2):341-4.

Convincing evidence from rodent models of carcinogenesis indicates that cis-9,trans-11 (c9t11) conjugated linoleic acid (CLA) is a potent naturally occurring anti-carcinogen in the human diet. CLA has been reported to alter the fatty acid composition of biological tissues in a manner that increases their oxidative stability. However, recent information suggests that an antioxidant role for CLA does not seem plausible. Given the knowledge that c9t11 CLA is present in a wide range of meat and dairy food products, our studies have begun to investigate mechanisms by which CLA-enriched milk fat exerts its anti-carcinogenic effects. An oxidative mechanism appears to be involved in its growth-suppressive effects, since supplementation of growth culture medium with CLA (17-71.5 microM) made breast cancer cells more susceptible to lipid peroxidation. Studies have indicated that cancer cells may become enriched in CLA during growth in culture. This may make intracellular lipids more susceptible to ordinary levels of oxidative stress, to the point of producing a cytotoxic effect

Some aspects of vitamin E related to humans and breast cancer prevention.

Dimitrov NV, Pan RQ, Bauer J, et al.

Adv Exp Med Biol. 1994; 364:119-27.

The biological activities of vitamin E are related to the cellular functions and presence of sufficient tissue concentrations of this micronutrient. Most of the stored vitamin E is in the adipose tissue where it appears to be distributed equally. The breast adipose tissue has similar vitamin E concentrations as other parts of the body. The ductal systems also store vitamin E in sufficient concentrations to maintain cellular functions. The milk secreted from the ducts of the breast contains a high concentration of tocopherol. Whereas the normal breast tissue presumably utilizes vitamin E as an antioxidant, tumor tissue appears to handle vitamin E differently. Breast tumors possessing estrogen negative receptors and having poor histological differentiation have lower concentrations of vitamin E than tumors with positive estrogen receptors and well differentiated histology. Since vitamin E is considered the principal, if not sole, chain-breaking lipophilic antioxidant in plasma and tissue, its role as a potential chemopreventive agent in breast cancer should be further investigated. The combination of vitamin E with other cancer chemopreventive agents appears to be a reasonable procedure

Estrogen receptor expression profile of disseminated epithelial tumor cells in bone marrow of breast cancer patients.

Ditsch N, Mayer B, Rolle M, et al.

Recent Results Cancer Res. 2003; 162:141-7.

The estrogen receptor (ER) status in primary breast cancer represents an important prognostic factor and has a profound impact on therapeutic decisions. However, ER expression profile on disseminated breast cancer cells is largely unknown, although these cells are one of the main target structures in adjuvant therapy after local curative resection (R0) achieved in most breast cancer patients. Thus, the present pilot study was designed to evaluate the ER expression profile on disseminated epithelial cells in bone marrow, one of the preferential organs for manifestation of distant metastases in breast cancer. Using the alkaline phosphatase anti-alkaline phosphatase-immunogold double staining procedure, in a panel of 17 breast cancer patients, epithelial cells (mab CK2) detected in bone marrow were analyzed for ER expression (mab 1D5) and compared with ER expression in the corresponding primary tumors. Whereas eleven of the 17 patients (64.7%) were ER-positive in primary carcinomas, only two patients (11.8%) revealed ER-positive epithelial cells in bone marrow. In addition, one of these two patients demonstrated a heterogeneous ER expression pattern, with both ER-positive and ER-negative epithelial cells in bone marrow. Although in both of these cases the ER-positive epithelial cells in bone marrow derived from ER-positive primary tumors, in this small patient cohort none of the prognostic relevant clinical and pathological factors tested, i.e., TNM-classification, grading, and ER status in primary breast cancer, correlated with the ER status in bone marrow. The striking discrepancy between ER expression in primary breast cancers and the corresponding disseminated epithelial cells in bone marrow suggests either the selective dissemination of ER-negative tumor cells into the bone marrow or a negative impact of the bone marrow microenvironment on epithelial ER expression. This phenomenon might influence therapeutic effects of antihormonal treatment

Traditional and alternative therapies for breast cancer.

Dog TL, Riley D, Carter T.

Altern Ther Health Med. 2001 May; 7(3):36-7.

Common benign conditions of the breast. In Cancer of the Breast, Fourth Edition 1995.

Donegan WL.

1995;

Characterization of the biological activity of gamma-glutamyl-Se-methylselenocysteine: a novel, naturally occurring anticancer agent from garlic.

Dong Y, Lisk D, Block E, et al.

Cancer Res. 2001 Apr 1; 61(7):2923-8.

Gamma-glutamyl-Se-methylselenocysteine (GGMSC) has recently been identified as the major Se compound in natural garlic and selenized garlic. Our working hypothesis is that GGMSC serves primarily as a carrier of Se-methylselenocysteine (MSC), which has been demonstrated in past research to be a potent cancer chemopreventive agent in animal carcinogenesis bioassays. The present study was designed to examine the in vivo responses to GGMSC or MSC using a variety of biochemical and biological end points, including (a) urinary Se excretion as a function of bolus dose; (b) tissue Se accumulation profile; (c) anticancer efficacy; and (d) gene expression changes as determined by cDNA array analysis. Our results showed that like MSC, GGMSC was well absorbed p.o., with urinary excretion as the major route for eliminating excess Se. When fed chronically, the profile of Se accumulation in various tissues was very comparable after treatment with either GGMSC or MSC. In rats that had been challenged with a carcinogen, supplementation with either GGMSC or MSC resulted in a lower prevalence of premalignant lesions in the mammary gland, and fewer mammary carcinomas when these early lesions were allowed to progress. More importantly, we found that a short term GGMSC/MSC treatment schedule of 4 weeks immediately after carcinogen dosing was sufficient to provide significant cancer protection, even in the absence of a sustained exposure past the initial 4-week period. With the use of the Clontech Atlas Rat cDNA Array, we further discovered that the gene expression changes induced in mammary epithelial cells of rats that were given either GGMSC or MSC showed a high degree of concordance. On the basis of the collective biology, biochemistry, and molecular biology data, we conclude that GGMSC is an effective anticancer agent with a mechanism of action very similar to that of MSC

Letrozole inhibits tumor proliferation more effectively than tamoxifen independent of HER1/2 expression status.

Ellis MJ, Coop A, Singh B, et al.

Cancer Res. 2003 Oct 1; 63(19):6523-31.

BACKGROUND: The biological basis for the superior efficacy of neoadjuvant letrozole versus tamoxifen for postmenopausal women with estrogen receptor (ER)-positive locally advanced breast cancer was investigated by analyzing tumor proliferation and expression of estrogen-regulated genes before and after the initiation of therapy. METHODS: Tumor samples were obtained at baseline and at the end of treatment from 185 patients participating in a double blind randomized Phase III study of neoadjuvant endocrine therapy. These paired specimens were simultaneously analyzed for Ki67, ER, progesterone receptor (PgR), trefoil factor 1 (PS2), HER1 (epidermal growth factor receptor), and HER2 (ErbB2 or neu) by semiquantitative immunohistochemistry. RESULTS: The treatment-induced reduction in geometric mean Ki67 was significantly greater with letrozole (87%) than tamoxifen (75%; analysis of covariance P = 0.0009). Differences in the average Ki67 reduction were particularly marked for ER-positive tumors that overexpressed HER1 and/or HER2 (88 versus 45%, respectively; P = 0.0018). Twenty-three of 92 tumors (25%) on tamoxifen and 14 of 93 on letrozole (15%) showed a paradoxical increase in Ki67 with treatment, and the majority of these cases was HER1/2 negative. Letrozole, but not tamoxifen, significantly reduced expression of the estrogen-regulated proteins PgR and trefoil factor 1, regardless of HER1/2 status (P < 0.0001). ER down-regulation occurred with both agents, although levels decreased more with tamoxifen (P < 0.0001). CONCLUSION: Letrozole inhibited tumor proliferation to a greater extent than tamoxifen. The molecular basis for this advantage appears complex but includes possible tamoxifen agonist effects on the cell cycle in both HER1/2+ and HER1/2- tumors. A pattern of continued proliferation despite appropriate down-regulation of PgR expression with estrogen deprivation or tamoxifen was also documented. This observation suggests the estrogenic regulation of proliferation and PgR expression may be dissociated in endocrine therapy resistant cells

Screening mammograms by community radiologists: variability in false-positive rates.

Elmore JG, Miglioretti DL, Reisch LM, et al.

J Natl Cancer Inst. 2002 Sep 18; 94(18):1373-80.

BACKGROUND: Previous studies have shown that the agreement among radiologists interpreting a test set of mammograms is relatively low. However, data available from real-world settings are sparse. We studied mammographic examination interpretations by radiologists practicing in a community setting and evaluated whether the variability in false-positive rates could be explained by patient, radiologist, and/or testing characteristics. METHODS: We used medical records on randomly selected women aged 40-69 years who had had at least one screening mammographic examination in a community setting between January 1, 1985, and June 30, 1993. Twenty-four radiologists interpreted 8734 screening mammograms from 2169 women. Hierarchical logistic regression models were used to examine the impact of patient, radiologist, and testing characteristics. All statistical tests were two-sided. RESULTS: Radiologists varied widely in mammographic examination interpretations, with a mass noted in 0%-7.9%, calcification in 0%-21.3%, and fibrocystic changes in 1.6%-27.8% of mammograms read. False-positive rates ranged from 2.6% to 15.9%. Younger and more recently trained radiologists had higher false-positive rates. Adjustment for patient, radiologist, and testing characteristics narrowed the range of false-positive rates to 3.5%-7.9%. If a woman went to two randomly selected radiologists, her odds, after adjustment, of having a false-positive reading would be 1.5 times greater for the radiologist at higher risk of a false-positive reading, compared with the radiologist at lowest risk (95% highest posterior density interval [similar to a confidence interval] = 1.17 to 2.08). CONCLUSION: Community radiologists varied widely in their false-positive rates in screening mammograms; this variability range was reduced by half, but not eliminated, after statistical adjustment for patient, radiologist, and testing characteristics. These characteristics need to be considered when evaluating false-positive rates in community mammographic examination screening

The chemoprevention of cancer by mevalonate-derived constituents of fruits and vegetables.

Elson CE, Yu SG.

J Nutr. 1994 May; 124(5):607-14.

Anutritive isoprenoid constituents of fruits, vegetables, cereal grains and essential oils exhibit a spectrum of anticarcinogenic activities. The induction of hepatic Phase II detoxifying activities by dietary isoprenoids appears to underlie their blocking action. The second anticarcinogenic action of the dietary isoprenoids, suppression of the growth of chemically initiated and transplanted tumors is, we suggest, secondary to the inhibition of mevalonate pathway activities. Mevinolin, a competitive inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase activity, depletes cells of the intermediate products of the pathway that are required for the posttranslational modification of proteins, a process giving the proteins lipophilic anchors that bind to membranes. As a consequence, nuclear lamins and ras oncoproteins remain in nascent states, and cells do not proliferate. gamma-Tocotrienol, perillyl alcohol, geraniol and d-limonene suppress hepatic HMG-CoA reductase activity, a rate-limiting step in cholesterol synthesis, and modestly lower serum-cholesterol levels of animals. These isoprenoids also suppress tumor growth. The HMG-CoA reductase of neoplastic tissues differs from that of sterologenic tissues in being markedly resistant to sterol feedback inhibition. Our review suggests that the mevalonate pathway of tumor tissues is uniquely sensitive to the inhibitory actions of the dietary isoprenoids

Reduced cancer incidence among the blind.

Feychting M, Osterlund B, Ahlbom A.

Epidemiology. 1998 Sep; 9(5):490-4.

Melatonin is a hormone primarily produced by the pineal gland at night and is suppressed by exposure to light. Experimental studies have indicated that melatonin may protect against cancer development. In the majority of totally blind people, melatonin is never suppressed by light exposure. The aim of this study was to test the hypothesis that blind people have a decreased cancer incidence, and that this effect is more pronounced in the totally blind than in the severely visually impaired. We identified a cohort of 1,567 totally blind and 13,292 severely visually impaired subjects and obtained information about cancer incidence from the Swedish Cancer Registry. We calculated standardized incidence ratios (SIRs) based on the number of person-years and incidence rates specific for national age, sex, and calendar year. Totally blind people had a lower incidence of all cancers combined [SIR = 0.69; 95% confidence interval (CI) = 0.59-0.82]. The risk reduction was observed in both men and women and was equally pronounced in hormone-dependent tumors as in other types of cancer. In the severely visually impaired, SIR was 0.95 (95% CI = 0.91-1.00). The findings support the hypothesis that blind people have a lower cancer incidence, although other explanations than the higher melatonin exposure must also be considered

Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study.

Fisher B, Costantino JP, Wickerham DL, et al.

J Natl Cancer Inst. 1998 Sep 16; 90(18):1371-88.

BACKGROUND: The finding of a decrease in contralateral breast cancer incidence following tamoxifen administration for adjuvant therapy led to the concept that the drug might play a role in breast cancer prevention. To test this hypothesis, the National Surgical Adjuvant Breast and Bowel Project initiated the Breast Cancer Prevention Trial (P-1) in 1992. METHODS: Women (N=13388) at increased risk for breast cancer because they 1) were 60 years of age or older, 2) were 35-59 years of age with a 5-year predicted risk for breast cancer of at least 1.66%, or 3) had a history of lobular carcinoma in situ were randomly assigned to receive placebo (n=6707) or 20 mg/day tamoxifen (n=6681) for 5 years. Gail's algorithm, based on a multivariate logistic regression model using combinations of risk factors, was used to estimate the probability (risk) of occurrence of breast cancer over time. RESULTS: Tamoxifen reduced the risk of invasive breast cancer by 49% (two-sided P<.00001), with cumulative incidence through 69 months of follow-up of 43.4 versus 22.0 per 1000 women in the placebo and tamoxifen groups, respectively. The decreased risk occurred in women aged 49 years or younger (44%), 50-59 years (51%), and 60 years or older (55%); risk was also reduced in women with a history of lobular carcinoma in situ (56%) or atypical hyperplasia (86%) and in those with any category of predicted 5-year risk. Tamoxifen reduced the risk of noninvasive breast cancer by 50% (two-sided P<.002). Tamoxifen reduced the occurrence of estrogen receptor-positive tumors by 69%, but no difference in the occurrence of estrogen receptor-negative tumors was seen. Tamoxifen administration did not alter the average annual rate of ischemic heart disease; however, a reduction in hip, radius (Colles'), and spine fractures was observed. The rate of endometrial cancer was increased in the tamoxifen group (risk ratio = "2.53;" 95% confidence interval = "1.35-4.97);" this increased risk occurred predominantly in women aged 50 years or older. All endometrial cancers in the tamoxifen group were stage I (localized disease); no endometrial cancer deaths have occurred in this group. No liver cancers or increase in colon, rectal, ovarian, or other tumors was observed in the tamoxifen group. The rates of stroke, pulmonary embolism, and deep-vein thrombosis were elevated in the tamoxifen group; these events occurred more frequently in women aged 50 years or older. CONCLUSIONS: Tamoxifen decreases the incidence of invasive and noninvasive breast cancer. Despite side effects resulting from administration of tamoxifen, its use as a breast cancer preventive agent is appropriate in many women at increased risk for the disease

Relevance of the biosynthesis of coenzyme Q10 and of the four bases of DNA as a rationale for the molecular causes of cancer and a therapy.

Folkers K.

Biochem Biophys Res Commun. 1996 Jul 16; 224(2):358-61.

In the human, coenzyme Q10 (vitamin Q10) is biosynthesized from tyrosine through a cascade of eight aromatic precursors. These precursors indispensably require eight vitamins, which are tetrahydrobiopterin, vitamins B6, C, B2, B12, folic acid, niacin, and pantothenic acid as their coenzymes. Three of these eight vitamins (the coenzyme B6, and the coenzymes niacin and folic acid) are indispensable in the biosynthesis of the four bases (thymidine, guanine, adenine, and cytosine) of DNA. One or more of the three vitamins required for DNA are known to cause abnormal pairing of the four bases, which can then result in mutations and the diversity of cancer. The coenzyme B6, required for the conversion of tyrosine to p-hydroxybenzoic acid, is the first coenzyme required in the cascade of precursors. A deficiency of the coenzyme B6 can cause dysfunctions, prior to the formation of vitamin Q10, to DNA. Former data on blood levels of Q10 and new data herein on blood levels of B6, measured as EDTA, in cancer patients established deficiencies of Q10 and B6 in cancer. This complete biochemistry relating to biosyntheses of Q10 and the DNA bases is a rationale for the therapy of cancer with Q10 and other entities in this biochemistry

Mutagenicity of low-filtered 30 kVp X-rays, mammography X-rays and conventional X-rays in cultured mammalian cells.

Frankenberg-Schwager M, Garg I, Fran-Kenberg D, et al.

Int J Radiat Biol. 2002 Sep; 78(9):781-9.

PURPOSE: To measure the mutagenic effectiveness of low-filtered 30 kVp X-rays, mammography X-rays and conventional (200 kVp) X-rays in mammalian cells. MATERIALS AND METHODS: Two different cell lines and mutation assays were used. Exponentially growing SV40-transformed human fibroblasts were exposed to graded doses of mammography (29 kVp, tungsten anode, 50 microm Rh filter) or conventional X-rays and the frequency of 6-thioguanine-resistent HPRT-deficient mutants was determined. Exponentially growing hamster A(L) cells, which contain a single human chromosome 11 conferring the expression of the human surface protein CD59, were subjected to magnetic cell separation (MACS) in order to remove spontaneous mutants before irradiation with low-filtered 30 kVp (tungsten anode, 0.5 mm Al filter) or conventional X-rays. Fractions of radiation-induced

Opposing effects of dietary n-3 and n-6 fatty acids on mammary carcinogenesis: The Singapore Chinese Health Study.

Gago-Dominguez M, Yuan JM, Sun CL, et al.

Br J Cancer. 2003 Nov 3; 89(9):1686-92.

We investigated the effects of individual fatty acids on breast cancer in a prospective study of 35,298 Singapore Chinese women aged 45-74 years, who were enrolled during April 1993 to December 1998 (The Singapore Chinese Health Study). At recruitment, each study subject was administered, in-person, a validated, semiquantitative food frequency questionnaire consisting of 165 food and beverage items. As of December 31, 2000, 314 incident cases of breast cancer had occurred. We used the Cox regression methods to examine individual fatty acids in relation to breast cancer risk, with adjustment for age at baseline interview, year of interview, dialect group, level of education, daily alcohol drinking, number of live births, age when menstrual periods became regular, and family history of breast cancer. Consumption of saturated, monounsaturated or polyunsaturated fat overall was unrelated to risk. On the other hand, high levels of dietary n-3 fatty acids from fish/shellfish (marine n-3 fatty acids) were significantly associated with reduced risk. Relative to the lowest quartile of intake, individuals in the higher three quartiles exhibited a 26% reduction in risk (relative risk (RR)=0.74, 95% confidence interval (CI)=0.58, 0.94)); RRs were similar across the top three quartiles of intake (0.75, 0.75, 0.72, respectively). Overall, there was no association between n-6 fatty acids and breast cancer risk. However, among subjects who consumed low levels of marine n-3 fatty acids (lowest quartile of intake), a statistically significant increase in risk was observed in individuals belonging to the highest vs the lowest quartile of n-6 fatty acid consumption (RR=1.87, 95% CI=1.06-3.27); the corresponding RR for advanced breast cancer was 2.45 (95% CI=1.20-4.97, P for trend=0.01). To our knowledge, these are the first prospective findings linking the intake of marine n-3 fatty acids to breast cancer protection

Endocrine disruption by indole-3-carbinol and tamoxifen: blockage of ovulation.

Gao X, Petroff BK, Oluola O, et al.

Toxicol Appl Pharmacol. 2002 Sep 15; 183(3):179-88.

Immature Sprague-Dawley rats received daily doses of indole-3-carbinol (I3C, 0-1.5 g/kg/day), 3,3'-diindolymethane (DIM, 0-400 mg/kg/day), tamoxifen (TAM, 0-0.5 mg/kg/day), or vehicle to determine if their antiestrogenic effects occur by the same mechanism and whether I3C's action is mediated by DIM. Follicular development was induced on day 24 of age by equine chorionic gonadotropin (eCG, 5 IU) 1 day after the initial dose. In a hormone replacement study, human chorionic gonadotropin (hCG, 10 IU sc, 48 h post-eCG) was used to mimic a normal preovulatoy luteinizing hormone (LH) surge following treatment with either I3C or TAM. Blood and ovaries were collected throughout follicular development and the number of ova shed was measured on the morning following expected ovulation (72 h post-eCG). I3C but not TAM reduced body weight gain at higher doses after 4 days of dosing. Ovarian weight gain and ovulation were inhibited by both I3C and TAM in a dose-dependent fashion. During the preovulatory period, both I3C and TAM blocked normal LH and follicle-stimulating hormone (FSH) surges and suppressed serum progesterone (P(4)) profoundly without changing circulating levels of estrogen (E(2)). At the time of expected ovulation, serum E(2) was increased in rats receiving I3C or tamoxifen, whereas serum P(4) was dose-dependently decreased. DIM exerted no significant effects on any of the endpoints studied, even at the highest dose, indicating that the antiestrogenic effects of I3C are not mediated by this metabolite of I3C. hCG successfully restored ovarian weight gain and ovulation in TAM-treated rats. However, hCG only partially reversed the blockage of ovulation by I3C, although ovarian weight gain was restored to normal. In summary, both I3C and TAM block ovulation by altering preovulatory concentrations of LH and FSH, but I3C appears to exert its effect(s) by (a) different mechanism(s) of action. I3C seems to act at both the ovarian and hypothalamic levels by mechanisms similar to those seen in TCDD-treated rats, whereas TAM appears to act only on the hypothalamic-pituitary axis as an anti-estrogen

Meeting highlights: updated international expert consensus on the primary therapy of early breast cancer.

Goldhirsch A, Wood WC, Gelber RD, et al.

J Clin Oncol. 2003 Sep 1; 21(17):3357-65.

This account of the highlights of the eighth St Gallen (Switzerland) meeting in 2003 emphasizes new information that has emerged during the 2 years since the seventh meeting in 2001. This article should be read in conjunction with the report of that earlier meeting. Recommendations for patient care are so critically dependent on assessment of endocrine responsiveness that the importance of high-quality steroid hormone receptor determination and standardized quantitative reporting cannot be overemphasized. The International Consensus Panel modified the risk categories so that only endocrine receptor-absent status was sufficient to reclassify an otherwise low-risk, node-negative disease into the category of average risk. Absence of steroid hormone receptors also was recognized as indicating endocrine nonresponsiveness. Some important areas highlighted at the recent meeting include: (1) recognition of the separate nature of endocrine-nonresponsive breast cancer-both invasive cancers and ductal carcinoma-in-situ; (2) improved understanding of the mechanisms of acquired endocrine resistance, which offer exciting prospects for extending the impact of successful sequential endocrine therapies; (3) presentation of high-quality evidence indicating that chemotherapy and tamoxifen should be used sequentially rather than concurrently; (4) availability of a potential alternative to tamoxifen for treatment of postmenopausal women with endocrine-responsive disease; and (5) the promise of newly defined prognostic and predictive markers

Dietary (n-3)/(n-6) fatty acid ratio: possible relationship to premenopausal but not postmenopausal breast cancer risk in U.S. women.

Goodstine SL, Zheng T, Holford TR, et al.

J Nutr. 2003 May; 133(5):1409-14.

Recent research has suggested that an increased (n-3) fatty acid intake and/or increased (n-3)/(n-6) polyunsaturated fatty acid (PUFA) ratio in the diet is associated with a lower breast cancer risk. This case-control study investigated the association between intake of (n-3) and other fatty acids and the (n-3)/(n-6) PUFA ratio and breast cancer risk. After combining data from two related case-control studies in Connecticut, we had information available on a total of 1119 women (565 cases and 554 controls). Cases were all histologically confirmed, incident breast carcinoma patients. Controls were hospital-based (Yale-New Haven Hospital study site) and population-based (Tolland County study site). Information on dietary intake was obtained through a validated food-frequency questionnaire. Standard multivariate methods were used to address the independent effects of specific fatty acids, fat classes and macronutrients on breast cancer risk. In the full study population, there were no significant trends for any macronutrient/fatty acid when comparing the highest to the lowest quartile of intake. When the analysis was restricted to premenopausal women, consumption of the highest compared with the lowest quartile of the (n-3)/(n-6) PUFA ratio was associated with a nonsignificant 41% lower risk of breast cancer [odds ratio (OR) = 0.59, 95% confidence interval (CI) 0.29, 1.19, P for trend = 0.09]. A higher (n-3)/(n-6) PUFA ratio was significantly associated with a lower risk of breast cancer when the data were restricted to the Tolland County (population-based) study site; OR = 0.50, 95% CI 0.27, 0.95, P for trend = 0.02. These results are consistent with the hypothesis that a higher (n-3)/(n-6) PUFA ratio may reduce the risk of breast cancer, especially in premenopausal women

A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer.

Goss PE, Ingle JN, Martino S, et al.

N Engl J Med. 2003 Nov 6; 349(19):1793-802.

BACKGROUND: In hormone-dependent breast cancer, five years of postoperative tamoxifen therapy--but not tamoxifen therapy of longer duration--prolongs disease-free and overall survival. The aromatase inhibitor letrozole, by suppressing estrogen production, might improve the outcome after the discontinuation of tamoxifen therapy. METHODS: We conducted a double-blind, placebo-controlled trial to test the effectiveness of five years of letrozole therapy in postmenopausal women with breast cancer who have completed five years of tamoxifen therapy. The primary end point was disease-free survival. RESULTS: A total of 5187 women were enrolled (median follow-up, 2.4 years). At the first interim analysis, there were 207 local or metastatic recurrences of breast cancer or new primary cancers in the contralateral breast--75 in the letrozole group and 132 in the placebo group--with estimated four-year disease-free survival rates of 93 percent and 87 percent, respectively, in the two groups (P< or ="0.001" for the comparison of disease-free survival). A total of 42 women in the placebo group and 31 women in the letrozole group died (P="0.25" for the comparison of overall survival). Low-grade hot flashes, arthritis, arthralgia, and myalgia were more frequent in the letrozole group, but vaginal bleeding was less frequent. There were new diagnoses of osteoporosis in 5.8 percent of the women in the letrozole group and 4.5 percent of the women in the placebo group (P="0.07);" the rates of fracture were similar. After the first interim analysis, the independent data and safety monitoring committee recommended termination of the trial and prompt communication of the results to the participants. CONCLUSIONS: As compared with placebo, letrozole therapy after the completion of standard tamoxifen treatment significantly improves disease-free survival

Chemoprevention of chemically-induced mammary carcinogenesis by indole-3-carbinol.

Grubbs CJ, Steele VE, Casebolt T, et al.

Anticancer Res. 1995 May; 15(3):709-16.

Indole-3-carbinol, a component of cruciferous vegetables, was evaluated for it efficacy in the prevention of chemically-induced mammary tumors using three different protocols. Because this compound was unstable, it was administered by gavage rather than in the diet. A preliminary dose range study revealed that dose levels of 100 and 50 mg/day, 5x/week, were not toxic to female Sprague-Dawley rats. Initial studies in the DMBA model showed that administering indole-3-carbinol during the initiation and promotion phases were highly effective chemopreventive methods (91-96% reduction in cancer multiplicity). Subsequent studies showed that the administration of indole-3-carbinol only during the initiation phase (7 days prior to until 7 days post DMBA) was also highly effective as a chemopreventive agent. Determination of enzyme levels in the livers of animals treated long-term with indole-3-carbinol showed high levels of induction of various phase I and phase II drug metabolizing enzymes. Finally, indole-3-carbinol when administered both prior to and after MNU (a direct acting carcinogen) caused a significant decrease (65%) in mammary tumor multiplicity. These results support previous studies that indole-3-carbinol can prevent mammary carcinogenesis by direct and indirect acting carcinogens. Therefore, indole-3-carbinol might be a good candidate for chemoprevention of breast cancer in women

Effect of Caffeine, a xanthine derivative, in the inhibition of experimental lung metastasis induced by B16F10 melanoma cells.

Gude RP, Menon LG, Rao SG.

J Exp Clin Cancer Res. 2001 Jun; 20(2):287-92.

Caffeine, a methyl xanthine derivative, was studied to assess the effect on B16F10 melanoma induced experimental metastasis. Caffeine was administered at a dose of 100 and 50 mg/kg body weight by both routes, to tumour bearing animals. Solid tumour reduction studies with Caffeine showed a significant reduction in tumour volume for 100 mg/kg dose by both oral and i.p. routes. The Caffeine treated metastatic tumour bearing animals significantly (p<0.001) inhibited lung tumour nodules. Serum sialic acid levels and lung hydroxyproline contents in the treated groups were significantly (p<0.001) low, when compared with the untreated control animals. In the present study, our results suggest that Caffeine inhibits solid tumour development and pulmonary experimental metastasis induced by B16F10 melanoma cells, in murine model

Alteration of p53 damage response by tamoxifen treatment.

Guillot C, Falette N, Courtois S, et al.

Clin Cancer Res. 1996 Sep; 2(9):1439-44.

Hormone therapy is often used in association with chemotherapy in the treatment of estrogen-responsive breast cancers. By using breast adenocarcinoma cell lines, we show that antiestrogen treatment leads to a dramatic decrease of p53 protein levels. This effect leads to a loss of wild-type p53 response to genotoxic treatment. This inhibition is assessed by the lack of p53 protein accumulation and the loss of the p53-dependent induction of p21(WAF1/CIP1) expression. Given that the effects of several anticancer agents are mediated through DNA damage, these observations suggest that antiestrogen treatment could modulate cellular response to chemotherapeutic agents

Inhibition of proliferation of estrogen receptor-negative MDA-MB-435 and -positive MCF-7 human breast cancer cells by palm oil tocotrienols and tamoxifen, alone and in combination.

Guthrie N, Gapor A, Chambers AF, et al.

J Nutr. 1997 Mar; 127(3):544S-8S.

Tocotrienols are a form of vitamin E, having an unsaturated isoprenoid side-chain rather than the saturated side-chain of tocopherols. The tocotrienol-rich fraction (TRF) from palm oil contains alpha-tocopherol and a mixture of alpha-, gamma- and delta-tocotrienols. Earlier studies have shown that tocotrienols display anticancer activity. We previously reported that TRF, alpha-, gamma- and delta-tocotrienols inhibited proliferation of estrogen receptor-negative MDA-MB-435 human breast cancer cells with 50% inhibitory concentrations (IC50) of 180, 90, 30 and 90 microg/mL, respectively, whereas alpha-tocopherol had no effect at concentrations up to 500 microg/mL. Further experiments with estrogen receptor-positive MCF-7 cells showed that tocotrienols also inhibited their proliferation, as measured by [3H] thymidine incorporation. The IC50s for TRF, alpha-tocopherol, alpha-, gamma- and delta-tocotrienols were 4, 125, 6, 2 and 2 microg/mL, respectively. Tamoxifen, a widely used synthetic antiestrogen inhibits the growth of MCF-7 cells with an IC50 of 0.04 microg/mL. We tested 1:1 combinations of TRF, alpha-tocopherol and the individual tocotrienols with tamoxifen in both cell lines. In the MDA-MB-435 cells, all of the combinations were found to be synergistic. In the MCF-7 cells, only 1:1 combinations of gamma- or delta-tocotrienol with tamoxifen showed a synergistic inhibitory effect on the proliferative rate and growth of the cells. The inhibition by tocotrienols was not overcome by addition of excess estradiol to the medium. These results suggest that tocotrienols are effective inhibitors of both estrogen receptor-negative and -positive cells and that combinations with tamoxifen should be considered as a possible improvement in breast cancer therapy

A critical evaluation of sentinel lymph node dissection in malignancy.

Haigh PIGAE.

2000; Updates(14):1-11.

Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice.

Hanahan D, Bergers G, Bergsland E.

J Clin Invest. 2000 Apr; 105(8):1045-7.

Breast cancer after treatment of Hodgkin's disease.

Hancock SL, Tucker MA, Hoppe RT.

J Natl Cancer Inst. 1993 Jan 6; 85(1):25-31.

BACKGROUND: Most studies of survivors of Hodgkin's disease have shown a low risk for subsequent breast cancer, even though much lower doses of radiation than those used for Hodgkin's disease have been shown to induce breast cancer in other settings. PURPOSE: This study quantifies the risk of breast cancer following Hodgkin's disease treatment according to age at treatment and type of treatment. METHODS: To evaluate the risk of breast cancer from irradiation, we reviewed records of 885 women treated for Hodgkin's disease between 1961 and 1990 (mean follow-up, 10 years). Risks for breast cancer incidence and mortality were calculated by comparison with expected rates for a general female population matched by age and race. RESULTS: Twenty-five patients have developed invasive breast cancer, yielding a relative risk (RR) of 4.1 (95% confidence interval [CI] = 2.5-5.7). An additional patient developed multifocal carcinoma in situ. Age at irradiation strongly influenced risk: RR was 136 for women treated before 15 years of age (95% CI = 34-371). RR declined with age at irradiation (P for trend < .0001), but the elevation remained statistically significant for subjects less than 30 years old at the time of irradiation (for those 15-24, RR = "19" [95% CI = "10.3-32];" for those 24-29, RR = "7" [95% CI = "3.2-14.4])." In women above 30 years of age, the risk was not elevated (RR = "0.7;" 95% CI = "0.2-1.8)." Risk of breast cancer increased significantly with time since treatment (P for trend < .0001). The RR was 2.0 (95% CI = "1.0-3.5)" with follow-up under 15 years and 13.6 (95% CI = "7.9-18.2)" with follow-up equal to or exceeding 15 years. The addition of mechlorethamine, vincristine, procarbazine, and prednisone chemotherapy to irradiation increased the risk within the first 15 years. Most breast cancers (22 of 26) arose within or at the margin of the radiation field and were infiltrating ductal carcinomas. Stage distribution and outcome suggest that the increased incidence was not solely attributable to vigilant screening. RR of death from breast cancer was 5.1 (95% CI = "2.2-10.0)." CONCLUSIONS: Women treated for Hodgkin's disease with radiation before 30 years of age are at markedly increased risk for breast cancer, with risk increasing dramatically more than 15 years after therapy. IMPLICATIONS: The high RR for development of breast cancer in women exposed to therapeutic radiation under 30 years of age raises important issues about optimal treatment strategies for patients with Hodgkin's disease, breast cancer, and other cancers

Malignant tumors of the breast.

Harris JRMMNL.

1997;( Section 2)

Bone mass, bone loss, and osteoporosis prophylaxis.

Heaney RP.

Ann Intern Med. 1998 Feb 15; 128(4):313-4.

The macrophage activating potential of ubiquinones. In Biomedical and Clinical Aspects of Coenzyme 1981, pp. 325-34.

Hogenauer GMPDJ.

1981;325-34.

Seasonal variation in the secretion of mammotrophic hormones in normal women and women with previous breast cancer.

Holdaway IM, Mason BH, Gibbs EE, et al.

Breast Cancer Res Treat. 1997 Jan; 42(1):15-22.

Hormones such as melatonin whose serum concentrations vary seasonally have been previously implicated in the growth of breast cancer. The present study was undertaken to identify possible seasonal variation in a range of mammotrophic hormones which could exert a chronobiologic influence in women with breast tumours. Fifteen premenopausal women with a history of previous breast cancer (BC subjects) and 10 control women underwent 2-hourly serum sampling for 24 h at both summer and winter solstice for measurement of melatonin, growth hormone (GH), insulin-like growth factor-I (IGF-I), cortisol, prolactin and thyrotrophin (TSH). Hormone secretion at the different seasons was compared by measuring the area under the 24 h serum hormone concentration x time curves and by time series analysis of summer-to-winter differences in hormone concentration. Control women had significantly higher GH and IGF-I levels in summer compared to winter and significantly higher cortisol secretion in winter than summer. In contrast, BC women had no significant seasonal difference in IGF-I concentrations and had a reversal of the normal seasonal pattern of melatonin secretion, although seasonal changes in GH production were similar to controls. Prolactin and TSH showed no significant summer/winter variation in either group. Thus, seasonal variations in hormone secretion seen in normal women were, with exception of GH, absent or reversed in women with a previous history of breast cancer. As a result these individuals may be exposed to an asynchronous hormonal stimulus which could influence tumour growth. These changes could reflect a constitutional abnormality in BC women or may have been induced by the previous breast tumour

Holland-Frei Cancer Medicine.

Holland JFKDWPRBRCJrFE.

2000;

Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. Protocol 19 Aredia Breast Cancer Study Group.

Hortobagyi GN, Theriault RL, Porter L, et al.

N Engl J Med. 1996 Dec 12; 335(24):1785-91.

BACKGROUND: Bisphosphonates such as pamidronate disodium inhibit osteoclast-induced bone resorption associated with cancer that has metastasized to bone. METHODS: Women with stage IV breast cancer who were receiving cytotoxic chemotherapy and had at least one lytic bone lesion were given either placebo or pamidronate (90 mg) as a two-hour intravenous infusion monthly for 12 cycles. Skeletal complications, including pathologic fractures, the need for radiation to bone or bone surgery, spinal cord compression, and hypercalcemia (a serum calcium concentration above 12 mg per deciliter [3.0 mmol per liter] or elevated to any degree and requiring treatment), were assessed monthly. Bone pain, use of analgesic drugs, performance status, and quality of life were assessed throughout the trial. RESULTS: The efficacy of treatment was evaluated in 380 of 382 randomized patients, 185 receiving pamidronate and 195 receiving placebo. The median time to the occurrence of the first skeletal complication was greater in the pamidronate group than in the placebo group (13.1 vs. 7.0 months, P=0.005), and the proportion of patients in whom any skeletal complication occurred was lower (43 percent vs. 56 percent, P = 0.008). There was significantly less increase in bone pain (P=0.046) and deterioration of performance status (P=0.027) in the pamidronate group than in the placebo group. Pamidronate was well tolerated. CONCLUSIONS: Monthly infusions of pamidronate as a supplement to chemotherapy can protect against skeletal complications in women with stage IV breast cancer who have osteolytic bone metastases

Suppression of c-Jun/AP-1 activation by an inhibitor of tumor promotion in mouse fibroblast cells.

Huang TS, Lee SC, Lin JK.

Proc Natl Acad Sci U S A. 1991 Jun 15; 88(12):5292-6.

Curcumin, a dietary pigment responsible for the yellow color of curry, is a potent inhibitor of tumor promotion by phorbol esters. Functional activation of transcriptional factor c-Jun/AP-1 is believed to play an important role in signal transduction of phorbol 12-myristate 13-acetate-induced tumor promotion. Suppression of the c-Jun/AP-1 activation by curcumin is observed in mouse fibroblast cells. In vitro experiments indicate that inhibition of c-Jun/AP-1 binding to its cognate motif by curcumin may be responsible for the inhibition of c-Jun/AP-1-mediated gene expression. These findings show that the effect of curcumin on phorbol 12-myristate 13-acetate-induced inflammation/tumor promotion could be studied at the molecular level

A Review of the Department of Defense's Program for Breast Cancer Research 1997.

IOM.Institute of Medicine/Committee to Review the Department of Defense's Breast Cancer Research Program.

1997

Comparison of selenium and sulfur analogs in cancer prevention.

Ip C, Ganther HE.

Carcinogenesis. 1992 Jul; 13(7):1167-70.

Several organoselenium compounds have been shown to have powerful anticarcinogenic activity. In view of certain similarities between selenium and sulfur biochemistry, we have evaluated the chemopreventive efficacy of three pairs of analogs using the 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumor model in rats. The compounds tested were selenocystamine/cysteamine, Semethylselenocysteine/S-methylcysteine, selenobetaine/sulfobetaine. In the first study, each agent was added to the basal AIN-76A diet and was given before and continued after DMBA treatment until the end. All three selenium compounds were active; a 50% inhibition was achieved at approximately 25 x 10(-6) mol/kg with Se-methylselenocysteine and selenobetaine and at approximately 40 x 10(-6) mol/kg with selenocystamine. In the sulfur series, only cysteamine and S-methylcysteine produced anticancer activity, and the levels required for comparable responses were 500- to 750-fold higher compared to the corresponding selenium analogs. Sulfobetaine was inactive even when present at near maximally tolerated levels. In the second study, Se-methylselenocysteine and S-methylcysteine were chosen for further examination during the initiation and post-initiation phases of mammary carcinogenesis. Se-Methylselenocysteine was effective when it was given either before or after DMBA administration. In contrast, S-methylcysteine was effective only after DMBA treatment. Thus, compared to the sulfur structural analogs, selenium compounds are much more active in cancer protection and may have a multi-modal mechanism in preventing cellular transformation as well as in delaying or inhibiting the expression of malignancy after carcinogen exposure

Conjugated linoleic acid-enriched butter fat alters mammary gland morphogenesis and reduces cancer risk in rats.

Ip C, Banni S, Angioni E, et al.

J Nutr. 1999 Dec; 129(12):2135-42.

Conjugated linoleic acid (CLA) is a potent cancer preventive agent in animal models. To date, all of the in vivo work with CLA has been done with a commercial free fatty acid preparation containing a mixture of c9,t11-, t10,c12- and c11,t13-isomers, although CLA in food is predominantly (80-90%) the c9,t11-isomer present in triacylglycerols. The objective of this study was to determine whether a high CLA butter fat has biological activities similar to those of the mixture of free fatty acid CLA isomers. The following four different endpoints were evaluated in rat mammary gland: 1) digitized image analysis of epithelial mass in mammary whole mount; 2) terminal end bud (TEB) density; 3) proliferative activity of TEB cells as determined by proliferating cell nuclear antigen immunohistochemistry; and 4) mammary cancer prevention bioassay in the methylnitrosourea model. It should be noted that TEB cells are the target cells for mammary chemical carcinogenesis. Feeding butter fat CLA to rats during the time of pubescent mammary gland development reduced mammary epithelial mass by 22%, decreased the size of the TEB population by 30%, suppressed the proliferation of TEB cells by 30% and inhibited mammary tumor yield by 53% (P < 0.05). Furthermore, all of the above variables responded with the same magnitude of change to both butter fat CLA and the mixture of CLA isomers at the level of CLA (0.8%) present in the diet. Interestingly, there appeared to be some selectivity in the uptake or incorporation of c9,t11-CLA over t10,c12-CLA in the tissues of rats given the mixture of CLA isomers. Rats consuming the CLA-enriched butter fat also consistently accumulated more total CLA in the mammary gland and other tissues (four- to sixfold increases) compared with those consuming free fatty acid CLA (threefold increases) at the same dietary level of intake. We hypothesize that the availability of vaccenic acid (t11-18:1) in butter fat may serve as the precursor for the endogenous synthesis of CLA via the Delta9-desaturase reaction. Further studies will be conducted to investigate other attributes of this novel dairy product

Methylselenocysteine modulates proliferation and apoptosis biomarkers in premalignant lesions of the rat mammary gland.

Ip C, Dong Y.

Anticancer Res. 2001 Mar; 21(2A):863-7.

In the rat mammary carcinogenesis model, premalignant lesions known as intraductal proliferations (IDPs) are detectable within a few weeks after carcinogen treatment. These early transformed colonies are the precursors for the eventual formation of carcinomas. Our past research indicated that methylselenocysteine added to the diet of rats reduced the development of IDPs of all sizes (the size of each IDP was estimated operationally by the number of 5-micron serial sections showing the same pathology). The appearance of an IDP lesion represents a balance between cell proliferation and cell death. The modulation of these two cellular events by methylselenocysteine was investigated. The abdominal-inguinal mammary gland was excised 6 weeks after MNU administration. Proliferation and apoptosis were evaluated by BrdU labeling and the TUNEL assay, respectively. The expression levels of several cell cycle and apoptosis regulatory proteins, including cyclin D1, cyclin A, p27, p16, bcl-2, box and bak, were also assessed. All of the above endpoints were quantified by immunohistochemistry in paraffin-embedded sections. The results showed that the magnitude of the response to methylselenocysteine intervention seemed to depend on the size of the IDP lesion. For the purpose of this study, the small and large lesions were classified as those containing 30 serial sections, respectively. With the small lesions, methylselenocysteine significantly inhibited BrdU labeling and the expression of cyclin D1 and cyclin A, but increased the expression of p27. Interesting, only p27 was upregulated in the larger IDP lesions, while BrdU labeling and the cyclins were not affected. It is possible that the transformed phenotype becomes less sensitive to selenium-mediated arrest of proliferation once it progresses to a more advanced pathological stage. In contrast, methylselenocysteine stimulated apoptosis (TUNEL assay) by 3 to 4 fold, and this increase was evident in both the small and large IDP lesions. Consistent with the induction of apoptosis, a reduced expression of bcl-2 was also observed in the methylselenocysteine group. In summary, our data suggest that exposure to methylselenocysteine blocks clonal expansion of premalignant lesions at an early stage. This is achieved by simultaneously modulating certain molecular pathways that are responsible for inhibiting cell proliferation and enhancing apoptosis

Conjugated linoleic acid inhibits proliferation and induces apoptosis of normal rat mammary epithelial cells in primary culture.

Ip MM, Masso-Welch PA, Shoemaker SF, et al.

Exp Cell Res. 1999 Jul 10; 250(1):22-34.

The trace fatty acid conjugated linoleic acid (CLA) inhibits rat mammary carcinogenesis when fed prior to carcinogen during pubertal mammary gland development or during the promotion phase of carcinogenesis. The following studies were done to investigate possible mechanisms of these effects. Using a physiological model for growth and differentiation of normal rat mammary epithelial cell organoids (MEO) in primary culture, we found that CLA, but not linoleic acid (LA), inhibited growth of MEO and that this growth inhibition was mediated both by a reduction in DNA synthesis and a stimulation of apoptosis. The effects of CLA did not appear to be mediated by changes in epithelial protein kinase C (PKC) since neither total activity nor expression nor localization of PKC isoenzymes alpha, beta II, delta, epsilon, eta, or zeta were altered in the epithelium of CLA-fed rats. In contrast, PKCs delta, epsilon, and eta were specifically upregulated and associated with a lipid-like, but acetone-insoluble, fibrillar material found exclusively in adipocytes from CLA-fed rats. Taken together, these observations demonstrate that CLA can act directly to inhibit growth and induce apoptosis of normal MEO and may thus prevent breast cancer by its ability to reduce mammary epithelial density and to inhibit the outgrowth of initiated MEO. Moreover, the changes in mammary adipocyte PKC expression and lipid composition suggest that the adipose stroma may play an important in vivo role in mediating the ability of CLA to inhibit mammary carcinogenesis

Prevention of mammary cancer with conjugated linoleic acid: role of the stroma and the epithelium.

Ip MM, Masso-Welch PA, Ip C.

J Mammary Gland Biol Neoplasia. 2003 Jan; 8(1):103-18.

Conjugated linoleic acid (CLA), found naturally in dairy products and ruminant meats, refers to isomers of octadecadienoic acid with conjugated double bonds. CLA inhibits both

[Vitamin A augmentation of the effects of chemotherapy in metastatic breast cancers after menopause. Randomized trial in 100 patients].

Israel L, Hajji O, Grefft-Alami A, et al.

Ann Med Interne (Paris). 1985; 136(7):551-4.

Vitamin A was administered to randomly allocated patients in a group of 100 patients with metastatic breast carcinoma treated by chemotherapy. The daily doses (given indefinitely) ranged from 350,000 to 500,000 IU according to body weight. A significant increase in the complete response rate was observed. When subgroups determined by menopausal status were considered, it was observed that serum retinol levels were only significantly increased in the post-menopausal group on high dose Vitamin A. Response rates, duration of response and projected survival were only significantly increased in this subgroup. The therapeutic and biological implications of these findings are discussed

Curcumin induces a p53-dependent apoptosis in human basal cell carcinoma cells.

Jee SH, Shen SC, Tseng CR, et al.

J Invest Dermatol. 1998 Oct; 111(4):656-61.

Curcumin, a potent antioxidant and chemopreventive agent, has recently been found to be capable of inducing apoptosis in human hepatoma and leukemia cells by way of an elusive mechanism. Here, we demonstrate that curcumin also induces apoptosis in human basal cell carcinoma cells in a dose- and time-dependent manner, as evidenced by internucleosomal DNA fragmentation and morphologic change. In our study, consistent with the occurrence of DNA fragmentation, nuclear p53 protein initially increased at 12 h and peaked at 48 h after curcumin treatment. Prior treatment of cells with cycloheximide or actinomycin D abolished the p53 increase and apoptosis induced by curcumin, suggesting that either de novo p53 protein synthesis or some proteins synthesis for stabilization of p53 is required for apoptosis. In electrophoretic mobility gel-shift assays, nuclear extracts of cells treated with curcumin displayed distinct patterns of binding between p53 and its consensus binding site. Supportive of these findings, p53 downstream targets, including p21(CIP1/WAF1) and Gadd45, could be induced to localize on the nucleus by curcumin with similar p53 kinetics. Moreover, we immunoprecipitated extracts from basal cell carcinoma cells with different anti-p53 antibodies, which are known to be specific for wild-type or mutant p53 protein. The results reveal that basal cell carcinoma cells contain exclusively wild-type p53; however, curcumin treatment did not interfere with cell cycling. Similarly, the apoptosis suppressor Bcl-2 and promoter Bax were not changed with the curcumin treatment. Finally, treatment of cells with p53 antisense oligonucleotide could effectively prevent curcumin-induced intracellular p53 protein increase and apoptosis, but sense p53 oligonucleotide could not. Thus, our data suggest that the p53-associated signaling pathway is critically involved in curcumin-mediated apoptotic cell death. This evidence also suggests that curcumin may be a potent agent for skin cancer prevention or therapy

Structure-activity relationships for G2 checkpoint inhibition by caffeine analogs.

Jiang X, Lim LY, Daly JW, et al.

Int J Oncol. 2000 May; 16(5):971-8.

Caffeine inhibits the G2 checkpoint activated by DNA damage and enhances the toxicity of DNA-damaging agents towards p53-defective cancer cells. The relationship between structure and G2 checkpoint inhibitio