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Life Extension Magazine November 2012

Breast Cancer

Omics underpins novel clues on VDR chemoprevention target in breast cancer.

Breast cancer is the commonest form of female malignancy among women in Western countries. The advent of genomic technologies has enhanced the diagnosis and the biological classification of such pathology. It has been demonstrated that cancer takes many years to be fully established. This long dormancy could represent a potential window for intervening with chemoprevention studies. Cancer chemoprevention is by definition the use of natural, synthetic, or biological chemical agents to reverse, suppress, or delay the genetic or other alterations that culminate in the appearance of the tumor phenotype. An important step for the success of chemoprevention is the identification of molecularly targeted agents to prevent cancer development. Currently, only two chemoprevention agents, raloxifene and tamoxifen, are used in clinical practice to prevent breast cancer. In this review, we will mainly focus on: (1) the application of genomic technologies for the identification and validation of molecular targets for chemoprevention; (2) the role of vitamin D and its cognate receptor VDR (vitamin D receptor) as a model for the molecularly targeted chemoprevention of breast cancer.

OMICS. 2011 Jun;15(6):337-46

Novel agents for the prevention of breast cancer: targeting transcription factors and signal transduction pathways.

Transformation of breast cells occurs through loss or mutation of tumor suppressor genes, or activation or amplification of oncogenes, leading to deregulation of signal transduction pathways, abnormal amplification of growth signals, and aberrant expression of genes that ultimately transform the cells into invasive cancer. The goal of cancer preventive therapy, or "chemoprevention," is to eliminate premalignant cells or to block the progression of normal cells into cancer. Multiple alterations in signal pathways and transcription factors are observed in mammary gland tumorigenesis. In particular, estrogen receptor (ER) deregulation plays a critical role in breast cancer development and progress, and targeting ER with selective ER modulators (SERMs) has achieved significant reduction of breast cancer incidence in women at high risk for breast cancer. However, not all breast cancer is prevented by SERMs, because 30-40% of the tumors are ER-negative. Other receptors for retinoids, vitamin D analogs and peroxisome proliferator-activiator, along with transcription factors such as AP-1, NF-kappaB, and STATs (signal transducers and activators of transcription) affect breast tumorigenesis. This is also true for the signal transduction pathways, for example cyclooxygenase 2 (Cox-2), HER2/neu, mitogen-activated protein kinase (MAPK), and PI3K/Akt. Therefore, proteins in pathways that are altered during the process of mammary tumorigenesis may be promising targets of future chemopreventive drugs. Many newly-developed synthetic or natural compounds/agents are now under testing in preclinical studies and clinical trials. Receptor selective retinoids, receptor tyrosine kinase inhibitors (TKIs), SERMs, Cox-2 inhibitors, and others are some of the promising novel agents for the prevention of breast cancer. The chemopreventive activity of these agents and other novel signal transduction inhibitors are discussed in this chapter.

J Mammary Gland Biol Neoplasia. 2003 Jan;8(1):45-73

Breast cancer prevention trials: large and small trials.

Breast cancer is the most common cancer among women in the United States, with 192,870 new cases and 40,170 deaths due to this disease estimated to have occurred 2009. An emphasis on prevention has been increasing in view of a persisting high incidence of disease. Seventy percent of breast cancers are estrogen receptor (ER)-positive, and are therefore presumed to be hormone-responsive and potentially treatable or preventable by anti-estrogenic agents. To date, the large, phase III randomized controlled breast cancer prevention trials have tested and are testing only hormonal drugs designed to antagonize the carcinogenic effect of endogenous estrogen; these agents are either selective estrogen receptor modulators (SERMs) or aromatase inhibitors (AIs). The SERMs, tamoxifen and raloxifene, have been shown in these large trials to reduce the risk of ER-positive breast cancers; prevention trials of AIs are ongoing. Interest is now focusing on developing agents with a broader spectrum of preventive activity, particularly with regard to ER-negative subtypes of breast cancer. A number of phase I and II trials using tissue-derived surrogate endpoint biomarkers (SEBs) as outcomes have been implemented. These smaller trials address prevention not only of ER-negative but also ER-positive breast cancers, since approximately 50% of the latter have been shown to be resistant to the estrogen-targeting drugs used in the large trials. Issues of importance in these smaller trials include choice of agent, selection of appropriate trial participants, trial design, method of access to breast tissue in women without cancer, selection and monitoring of SEBs, and monitoring of drug toxicity.

Semin Oncol. 2010 Aug;37(4):367-83

Bioactive dietary supplements reactivate ER expression in ER-negative breast cancer cells by active chromatin modifications.

Breast cancer is the most common cancer and the leading cause of cancer death in women. Although tamoxifen therapy is successful for some patients, it does not provide adequate benefit for those who have estrogen receptor (ER)-negative cancers. Therefore, we approached novel treatment strategies by combining two potential bioactive dietary supplements for the reactivation of ERα expression for effective treatment of ERα-negative breast cancer with tamoxifen. Bioactive dietary supplements such as green tea polyphenols (GTPs) and sulforaphane (SFN) inhibit DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), respectively, which are of central importance to cancer prevention. In the present study, we have observed that treatment of ERα-negative breast cancer cells with GTPs and SFN alone or in combination leads to the reactivation of ERα expression. The combination of 20 µg/mL GTPs and 5 µM SFN was found to be the optimal dose of ERα-reactivation at 3 days in MDA-MB-231 cells. The reactivation of ERα expression was consistently correlated with ERα promoter hypomethylation and hyperacetylation. Chromatin immunoprecipitation (ChIP) analysis of the ERα promoter revealed that GTPs and SFN altered the binding of ERα-transcriptional co-repressor complex thereby contributing to ERα-reactivation. In addition, treatment with tamoxifen in combination with GTPs and SFN significantly increased both cell death and inhibition of cellular proliferation in MDA-MB-231 cells in comparison to treatment with tamoxifen alone. Collectively, our findings suggest that a novel combination of bioactive-HDAC inhibitors with bioactive-demethylating agents is a promising strategy for the effective treatment of hormonal refractory breast cancer with available anti-estrogens.

PLoS One. 2012;7(5):e37748. Epub 2012 May 25

Expression profiles of apoptotic genes induced by curcumin in human breast cancer and mammary epithelial cell lines.

Curcumin (diferuloyl methane), the yellow-colored dietary pigment from the rhizomes of turmeric, has been recognized as a chemopreventive agent because of its antitumor, antioxidant and antiproliferative effects. The cytotoxic, apoptotic and gene regulatory effects of both turmeric and curcumin were investigated in the MCF-7 human breast cancer carcinoma cell line and compared with the effects in MCF-10A human mammary epithelial cells. MCF-7 cells were more sensitive to turmeric and curcumin than MCF-10A cells. MCF-10A cells retained comparatively less curcumin in the medium than MCF- 7 cells after 24 h, thereby reducing the cytotoxic effect. Curcumin induced a significantly higher percentage of apoptosis in MCF-7 than MCF-10A cells at all doses. Microarray hybridization of Clonetech apoptotic arrays with labeled first-strand probes of total RNA was performed to identify and characterize the genes regulated by curcumin in tumor cells. Of the 214 apoptosis-associated genes in the array, the expression of 104 genes was altered by curcumin treatment. The gene expression was altered up to 14-fold levels in MCF-7 as compared to only up to 1.5-fold in the MCF-10A cell line by curcumin. Curcumin up-regulated (>3 fold) 22 genes and down-regulated (<3-fold) 17 genes at both 25 microg/ml and 50 microg/ml doses in the MCF-7 cell line. The up-regulated genes include HIAP1, CRAF1, TRAF6, CASP1, CASP2, CASP3, CASP4, HPRT, GADD45, MCL-1, NIP1, BCL2L2, TRAP3, GSTP1, DAXX, PIG11, UBC, PIG3, PCNA, CDC10, JNK1 and RBP2. The down-regulated genes were TRAIL, TNFR, AP13, IGFBP3, SARP3, PKB, IGFBP, CASP7, CASP9, TNFSF6, TRICK2A, CAS, TRAIL-R2, RATS1, hTRIP, TNFb and TNFRSF5. While a dose-dependent gene expression change was noticed in some genes, opposite regulatory effects were induced by different curcumin doses in three apoptotic genes. These results suggest that curcumin induces apoptosis in breast cancer cells by regulation of multiple signaling pathways, indicating its potential use for prevention and treatment of cancer.

Anticancer Res. 2005 Sep-Oct;25(5):3293-302

Dietary omega-3 polyunsaturated fatty acids suppress expression of EZH2 in breast cancer cells.

The polycomb group (PcG) protein, enhancer of zeste homologue 2 (EZH2), is overexpressed in several human malignancies including breast cancer. Aberrant expression of EZH2 has been associated with metastasis and poor prognosis in cancer patients. Despite the clear role of EZH2 in oncogenesis and therapy failure, not much is known about chemotherapeutics and chemopreventive agents that can suppress its expression and activity. Here, we show that dietary omega-3 (omega-3) polyunsaturated fatty acids (PUFAs) can regulate the expression of EZH2 in breast cancer cells. The treatment of breast cancer cells with omega-3 PUFAs, but not omega-6 PUFAs, led to downregulation of EZH2. Studies using proteosome inhibitor MG132 suggested that omega-3 PUFAs induce degradation of the PcG protein EZH2 through posttranslational mechanisms. Furthermore, downregulation of EZH2 by omega-3 PUFAs was accompanied by a decrease in histone 3 lysine 27 trimethylation (H3K27me3) activity of EZH2 and upregulation of E-cadherin and insulin-like growth factor binding protein 3, which are known targets of EZH2. Treatment with omega-3 PUFAs also led to decrease in invasion of breast cancer cells, an oncogenic phenotype that is known to be associated with EZH2. Thus, our studies suggest that the PcG protein EZH2 is an important target of omega-3 PUFAs and that downregulation of EZH2 may be involved in the mediation of anti-oncogenic and chemopreventive effects of omega-3 PUFAs.

Carcinogenesis. 2010 Mar;31(3):489-95

Modulation of gene methylation by genistein or lycopene in breast cancer cells.

Dietary agents with chemopreventive potential, including soy-derived genistein and tomato-derived lycopene, have been shown to alter gene expression in ways that can either promote or potentially inhibit the carcinogenic processes. To begin to explore the mechanisms by which these agents may be acting we have examined the DNA methylation modulating capacity of genistein or lycopene for several genes relevant to breast cancer in the breast cancer cell lines MCF-7 and MDA-MB-468, as well as in immortalized but noncancer fibrocystic MCF10A breast cells. We find using methylation specific PCR (MSP) that a low, nontoxic concentration of genistein (3.125 microM, resupplemented every 48 hr for 1 week) or a single dose of lycopene (2 microM) partially demethylates the promoter of the GSTP1 tumor suppressor gene in MDA-MB-468 cells. RT-PCR studies confirm a lack of GSTP1 expression in untreated MDA-MB-468, with restoration of GSTP1 expression after genistein or lycopene treatment. The RARbeta2 gene however, was not demethylated by genistein or lycopene in either of these breast cancer cell lines. But, lycopene (2 microM, once per week for 2 weeks) did induce demethylation of RARbeta2 and the HIN-1 genes in the noncancer MCF10A fibrocystic breast cells. These data show for the first time that the tomato carotenoid lycopene has direct DNA demethylating activity. In summary, both genistein and lycopene, at very low, dietarily relevant concentrations can potentially mitigate tumorigenic processes via promoter methylation modulation of gene expression.

Environ Mol Mutagen. 2008 Jan;49(1):36-45

Acetylated STAT3 is crucial for methylation of tumor-suppressor gene promoters and inhibition by resveratrol results in demethylation.

The mechanisms underlying hypermethylation of tumor-suppressor gene promoters in cancer is not well understood. Here, we report that lysine acetylation of the oncogenic transcription factor STAT3 is elevated in tumors. We also show that genetically altering STAT3 at Lys685 reduces tumor growth, which is accompanied by demethylation and reactivation of several tumor-suppressor genes. Moreover, mutating STAT3 at Lys685 disrupts DNA methyltransferase 1-STAT3 interactions in cultured tumor cells and in tumors. These observations are confirmed by treatment with an acetylation inhibitor, resveratrol. Furthermore, reduction of acetylated STAT3 in triple-negative breast cancer cells leads to demethylation and activation of the estrogen receptor-α gene, sensitizing the tumor cells to antiestrogens. Our results also demonstrate a correlation between STAT3 acetylation and methylation of estrogen receptor-α in melanoma, which predicts melanoma progression. Taken together, these results suggest a role of STAT3 acetylation in regulating CpG island methylation, which may partially explain aberrant gene silencing in cancer. These findings also provide a rationale for targeting acetylated STAT3 for chemoprevention and cancer therapy.

Proc Natl Acad Sci U S A. 2012 May 15;109(20):7765-9

Inhibition of DNA methylation by caffeic acid and chlorogenic acid, two common catechol-containing coffee polyphenols.

We studied the modulating effects of caffeic acid and chlorogenic acid (two common coffee polyphenols) on the in vitro methylation of synthetic DNA substrates and also on the methylation status of the promoter region of a representative gene in two human cancer cells lines. Under conditions that were suitable for the in vitro enzymatic methylation of DNA and dietary catechols, we found that the presence of caffeic acid or chlorogenic acid inhibited in a concentration-dependent manner the DNA methylation catalyzed by prokaryotic M.SssI DNA methyltransferase (DNMT) and human DNMT1. The IC50 values of caffeic acid and chlorogenic acid were 3.0 and 0.75 microM, respectively, for the inhibition of M.SssI DNMT-mediated DNA methylation, and were 2.3 and 0.9 microM, respectively, for the inhibition of human DNMT1-mediated DNA methylation. The maximal in vitro inhibition of DNA methylation was approximately 80% when the highest concentration (20 microM) of caffeic acid or chlorogenic acid was tested. Kinetic analyses showed that DNA methylation catalyzed by M.SssI DNMT or human DNMT1 followed the Michaelis-Menten curve patterns. The presence of caffeic acid or chlorogenic acid inhibited DNA methylation predominantly through a non-competitive mechanism, and this inhibition was largely due to the increased formation of S-adenosyl-L-homocysteine (SAH, a potent inhibitor of DNA methylation), resulting from the catechol-O-methyltransferase (COMT)-mediated O-methylation of these dietary catechols. Using cultured MCF-7 and MAD-MB-231 human breast cancer cells, we also demonstrated that treatment of these cells with caffeic acid or chlorogenic acid partially inhibited the methylation of the promoter region of the RARbeta gene. The findings of our present study provide a general mechanistic basis for the notion that a variety of dietary catechols can function as inhibitors of DNA methylation through increased formation of SAH during the COMT-mediated O-methylation of these dietary chemicals.

Carcinogenesis. 2006 Feb;27(2):269-77

Epigenetic diet: impact on the epigenome and cancer.

A number of bioactive dietary components are of particular interest in the field of epigenetics. Many of these compounds display anticancer properties and may play a role in cancer prevention. Numerous studies suggest that a number of nutritional compounds have epigenetic targets in cancer cells. Importantly, emerging evidence strongly suggests that consumption of dietary agents can alter normal epigenetic states as well as reverse abnormal gene activation or silencing. Epigenetic modifications induced by bioactive dietary compounds are thought to be beneficial. Substantial evidence is mounting proclaiming that commonly consumed bioactive dietary factors act to modify the epigenome and may be incorporated into an 'epigenetic diet.' Bioactive nutritional components of an epigenetic diet may be incorporated into one's regular dietary regimen and used therapeutically for medicinal or chemopreventive purposes. This article will primarily focus on dietary factors that have been demonstrated to influence the epigenome and that may be used in conjunction with other cancer prevention and chemotherapeutic therapies.

Epigenomics. 2011 Aug;3(4):503-18

Combination of photodynamic therapy + immunotherapy + chemotherapy in murine leukiemia.

Photodynamic therapy (PDT) is a treatment for cancer based on the photosensitization of tumor cells by photosensitive drugs and their subsequent destruction on exposure to light of particular wavelength. The combination of drug uptake in malignant tissues and selective delivery of laser-generated light provides an effective therapy with efficient tumor citotoxicity and minimal normal tissue damage. Since immune response of the host is important in the control of tumor growth and spreading, PDT is able to increase the antitumor immunity. In our laboratory we examined the antitumor effect of combination of PDT, with photoactivated M-THPC (meta-tetrahydroxyphenylchlorin, FOSCAN, Temoporphirin), adoptive immunotherapy, with immune lymphocytes, and chemotherapy on advanced murine tumors. Mice bearing L1210 tumor were treated at day +4 with Navelbine (NVB 1mg/Kg), at day +5,+6 with PDT (0.3mg/Kg of mTHPC and 100mW/cm(2) x 200'' of exposure of laser light), and at day + 7 with immune lymphocytes(IL), collected from mice pretreated with PDT(2x10(7) cells). The results show that the combination NVB + PDT + IL demonstrates a significant synergistic antitumor effect while the chemotherapy treatment with low dose of the drug is uneffective. The same positive results were obtained with the combination of Cisplatin (CDDP 0.5mg/Kg), PDT and IL, while the CDDP treatment alone is completely uneffective. In conclusion, these results suggest that it is possible to completely cure animals bearing advanced tumors, with a combined therapy, PDT + adoptive immunotherapy + low dose chemotherapy.

Neoplasma. 2010;57(2):184-8

Photodynamic therapy: the development of new photosensitisers.

The first 20 years of anticancer photodynamic therapy (PDT) were based on the utility of the oligomeric mixture haematoporphyrin derivative (HpD) in various forms. More recently new derivatives have become available, both porphyrin-derived and employing new chromophores, for example from the phthalocyanine and phenothiazinium families. In addition, a major research effort has been rewarded with the clinical acceptance of the porphyrin precursor 5-aminolaevulinic acid (ALA). New photosensitisers intended for clinical use must exhibit advantageous drug performance profiles compared to the first-generation porphyrin derivatives. This can be seen, in vitro, in improved photophysical properties such as the extension of the useful light absorption spectrum into the near infrared - offering greater tissue penetration - as well as in the synthesis of pure compounds rather than mixtures. In this review, recent developments in photosensitiser families are discussed with respect to in vitro performance indicators and to potential application in oncology.

Anticancer Agents Med Chem. 2008 Apr;8(3):280-91

Killer beacons for combined cancer imaging and therapy.

Precisely localizing therapeutic agents in neoplastic areas would greatly improve their efficacy for killing tumor cells and reduce their toxicity to normal cells. Photodynamic therapy (PDT) is a promising cancer treatment modality, and near-infrared fluorescence imaging (NIRF-I) is a sensitive and noninvasive approach for in vivo cancer detection. This review focuses on the current efforts to engineer single molecule constructs that allow these two modalities to be combined to achieve a high level of selectivity for cancer treatment. The primary component of these so called killer beacons is a fluorescent photosensitizer responsible for both imaging and therapy. By attaching other components, e.g. various DNA- or peptide-based linkers, quenchers or cancer cell-specific delivery vehicles, their primary diagnostic and therapeutic functions as well as their target specificity and pharmacological properties can be modulated. This modular design makes these agents customizable, offering the ability to assemble a few simple and often interchangeable functional modules into beacons with totally different functions. This review will summarize following three types of killer beacons: photodynamic molecular beacons, traceable beacons and beacons with built-in apoptosis sensor. Despite the rapid progress in killer beacon development, numerous challenges remain before these beacons can be translated into clinics, such as photobleaching, delivery efficiency and cancer-specificity. In this review we outline the basic principles of killer beacons, the current achievements and future directions, including possible cancer targets and different therapeutic applications.

Curr Med Chem. 2007;14(20):2110-25

Enhancement of laser cancer treatment by a chitosan-derived immunoadjuvant.

A chitosan derivative, glycated chitosan (GC), has been used as an immunostimulant for cancer treatment in laser immunotherapy. The function of GC is to enhance the host immune response after direct cancer cell destruction by a selective laser photothermal interaction. To further test its effects, laser immunotherapy was extended to include several different adjuvants for immunological stimulation and to include photodynamic therapy (PDT) as a different tumor-destruction mechanism. Complete Freund (CF) adjuvant, incomplete Freund (IF) adjuvant and Corynebacterium parvum (CP) were selected for treatment of metastatic mammary tumors in rats, in combination with a selective photothermal interaction. The solution of the immunoadjuvants admixed with indocyanine green (ICG), a light-absorbing dye, was injected directly into the tumors, followed by noninvasive irradiation of an 805 nm laser. Combined with PDT, in the treatment of tumors in mice, GC was administered peritumorally immediately after laser irradiation. The survivals of treated animals were compared with untreated control animals. In the treatment of rat tumors, CF, IF and CP raised the cure rates from 0% to 18%, 7% and 9%, respectively. In comparison, GC resulted in a 29% long-term survival. In the treatment of EMT6 mammary sarcoma in mice, GC of 0.5% and 1.5% concentrations increased the cure rates of Photofrin-based PDT treatment from 38% to 63% and 75%, respectively. In the treatment of Line 1 lung adenocarcinoma in mice, a 1.67% GC solution enabled a noncurative meso-substituted tetra(meta-hydroxy-phenyl)chlorin-based PDT to cure 37% of the tumor-bearing mice. The experimental results of this study confirmed our previous studies, showing that immunoadjuvants played an active role in laser-related cancer treatment and that GC significantly enhanced the efficacy of laser cancer treatment.

Photochem Photobiol. 2005 Jan-Feb;81(1):190-5

Photodynamic therapy: illuminating the road from cell death towards anti-tumour immunity.

Photodynamic therapy (PDT) utilizes the destructive power of reactive oxygen species generated via visible light irradiation of a photosensitive dye accumulated in the cancerous tissue/cells, to bring about their obliteration. PDT activates multiple signalling pathways in cancer cells, which could give rise to all three cell death modalities (at least in vitro). Simultaneously, PDT is capable of eliciting various effects in the tumour microenvironment thereby affecting the tumour-associated/-infiltrating immune cells and by extension, leading to infiltration of various immune cells (e.g. neutrophils) into the treated site. PDT is also associated to the activation of different immune phenomena, e.g. acute-phase response, complement cascade and production of cytokines/chemokines. It has also come to light that, PDT is capable of activating 'anti-tumour adaptive immunity' in both pre-clinical as well as clinical settings. Although the ability of PDT to induce 'anti-cancer vaccine effect' is still debatable, yet it has been shown to be capable of inducing exposure/release of certain damage-associated molecular patterns (DAMPs) like HSP70. Therefore, it seems that PDT is unique among other approved therapeutic procedures in generating a microenvironment suitable for development of systemic anti-tumour immunity. Apart from this, recent times have seen the emergence of certain promising modalities based on PDT like-photoimmunotherapy and PDT-based cancer vaccines. This review mainly discusses the effects exerted by PDT on cancer cells, immune cells as well as tumour microenvironment in terms of anti-tumour immunity. The ability of PDT to expose/release DAMPs and the future perspectives of this paradigm have also been discussed.

Apoptosis. 2010 Sep;15(9):1050-71

Induced antitumor immunity against DMBA-4 metastatic mammary tumors in rats using laser immunotherapy.

Induced antitumor immunity is a highly effective and long-term cure for cancer, particularly for metastatic tumors. Laser immunotherapy was developed to induce such an immunologic response. It involves intratumoral administration of a light-absorbing dye and a specially formulated immunoadjuvant, followed by noninvasive irradiation of a near-infrared laser. Treatment of DMBA-4 metastatic mammary tumors in rats with this approach has resulted in local control of primary tumors and eradication of untreated distant metastases. After laser immunotherapy, rats were resistant to tumor rechallenge and developed immunity, which could be adoptively transferred. To better understand the immunity induced in this tumor model, immunization using freeze-thaw DMBA-4 cell lysates was performed, followed by tumor challenge 21 days later. Tumor cell lysate immunization delayed the emergence of metastases but did not provide immunity against the tumor challenge. Also performed was surgical resection of primary tumors before the observation of metastatic tumors. Removal of primary tumors was unsuccessful at changing the course of tumor progression. Tumors re-emerged at the primary sites, and metastases developed at multiple remote sites. In contrast, tumor-bearing rats successfully treated by laser immunotherapy experienced tumor regression and eradication and developed strong resistance to repeated challenges by tumor cells of the same type. Our results show that laser immunotherapy could have potential for the treatment of metastatic tumors by inducing tumor-specific, long-lasting immunity.

Int J Cancer. 2003 Dec 20;107(6):1053-7

Clinical course of 771 patients with bilateral breast cancer: characteristics associated with overall and recurrence-free survival.

PURPOSE: Despite numerous retrospective and case-control studies, risk factors related to overall survival (OS) and recurrence-free survival (RFS) in bilateral breast cancer are still being defined. The aim of our study was to describe tumor properties, patient characteristics, and method of cancer detection for a large cohort of patients with bilateral breast cancer and to assess the associations of these factors with OS and RFS. PATIENTS AND METHODS: A retrospective chart review was conducted at the University of Texas M. D. Anderson Cancer Center. Among patients with bilateral breast cancer, we compared primary versus contralateral tumors and synchronous versus metachronous cancers. Patient and second tumor characteristics were evaluated for an association with OS and RFS, as measured from diagnosis of the second tumor. RESULTS: Of 11,234 patients with primary breast cancer seen for an initial visit between July 1, 1997, and December 31, 2004, 771 patients (6.9%) were diagnosed with bilateral breast cancer. The 5-year OS rates based on stage of the second tumor were 87.7%, 87.7%, 69.6%, 45.1%, and 23.8% for stages 0, I, II, III, and IV, respectively (P < .0001). The 5-year OS rates for second tumor detection via mammogram/prophylactic mastectomy, physical examination, and self-examination were 81.6%, 70.9%, and 65.3%, respectively (P = .01). In addition, lymphovascular invasion, nuclear grade, hormonal receptor status, and histology were significantly associated with OS and RFS (P < .05). In a multivariable analysis, clinical stage and lymphovascular invasion remained significantly associated with OS (P < .05). CONCLUSION: This study represents the largest single-institution review of bilateral breast cancer. Numerous second tumor characteristics were associated with survival. The results emphasize the importance of earlier detection and improved staging for contralateral breast cancer.

Clin Breast Cancer. 2007 Dec;7(11):867-74

Interaction of current cancer treatments and the immune system: implications for breast cancer therapeutics.

Early diagnosis and treatment of breast cancer may account for the current improvement in the mortality of breast cancer. However, achieving a complete 'cure' is the holy grail of cancer medicine and, in many cases, cancer patients still succumb to their ultimate fate. There is therefore a need to devise innovative therapies to overcome this problem. To this end, many emerging therapies utilizing the immune system to eradicate the residues of disease have been described in the preclinical and clinical arenas. However, there is very little work examining the impact of immunotherapy on the existing natural immunity. The relationship between antitumor immunity, in the form of immunotherapy (either passive or active), and current strategies of treatment also needs to be explored. If we are to improve the success of cancer treatment, we must understand how current therapies interact with the immune system and with the emerging immunotherapies. For breast-cancer treatment to be successful, therapeutics should be tailored towards antitumor immunity; they should also avoid tumor-specific tolerance. The sources of information used to prepare this paper were obtained through published work on Pubmed/Medline and materials published on the US/UK governmental agencies' websites.

Expert Opin Pharmacother. 2008 Oct;9(15):2639-60

A prophylactic vaccine for breast cancer?

Cancer vaccines are the Holy Grail for patients and clinicians alike. The possibility that we can be vaccinated against common cancers is very appealing and the socioeconomic consequences are significant. A recent paper from Vincent Tuohy's group, published in the journal Nature Medicine, suggests a new approach for the development of a prophylactic vaccine for breast cancer. Their strategy was to induce mammary gland failure in mice by immunisation with an antibody specific to a milk protein that resulted in autoimmunity during lactation. This also showed some efficacy as a therapeutic vaccine. Can we look forward to the elimination of breast cancer?

Breast Cancer Res. 2010;12(4):310

Molecular definition of breast tumor heterogeneity.

Cells with distinct phenotypes including stem-cell-like properties have been proposed to exist in normal human mammary epithelium and breast carcinomas, but their detailed molecular characteristics and clinical significance are unclear. We determined gene expression and genetic profiles of cells purified from cancerous and normal breast tissue using markers previously associated with stem-cell-like properties. CD24+ and CD44+ cells from individual tumors were clonally related but not always identical. CD44+ cell-specific genes included many known stem-cell markers and correlated with decreased patient survival. The TGF-beta pathway was specifically active in CD44+ cancer cells, where its inhibition induced a more epithelial phenotype. Our data suggest prognostic relevance of CD44+ cells and therapeutic targeting of distinct tumor cell populations.

Cancer Cell. 2007 Mar;11(3):259-73