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LE Magazine October 2008

Breast cancer

Targets of vitamin D receptor signaling in the mammary gland.

Since the discovery of the vitamin D receptor (VDR) in mammary cells, the role of the vitamin D signaling pathway in normal glandular function and in breast cancer has been extensively explored. In vitro studies have shown that the VDR ligand, 1,25-dihydroxyvitamin D (1,25D), modulates key proteins involved in signaling proliferation, differentiation, and survival of normal mammary epithelial cells. Similar anti-proliferative and pro-differentiating effects of 1,25D have been observed in VDR-positive breast cancer cells, indicating that transformation per se does not abolish vitamin D signaling. However, many transformed breast cancer lose sensitivity to 1,25D secondary to alterations in vitamin D metabolizing enzymes or downregulation of VDR function. Over the years, our laboratory has focused on three general areas: (1) defining mechanisms of vitamin D-mediated apoptosis in breast cancer cells, (2) examining changes in the vitamin D signaling pathway during transformation, including the development of vitamin D resistance, and (3) using mouse models to study the impact of the VDR on growth regulatory pathways in the context of development and tumorigenesis in vivo. Recent developments include detection of megalin-mediated uptake of vitamin D-binding protein (DBP) and identification of CYP27B1 and CYP24 metabolizing enzymes in mammary cells, demonstration of precocious mammary gland development in VDR-null mice, and identification of novel pathways triggered by 1,25D during apoptosis. Our preclinical studies have been complemented by emerging data from other groups suggesting that human breast cancer may be influenced by VDR genotype and vitamin D status. Collectively, these studies have reinforced the need to further define the regulation and function of the vitamin D pathway in cells in relation to prevention and treatment of breast cancer.

J Bone Miner Res. 2007 Dec;22 Suppl 2:V86-90

Vitamin D intake and breast cancer risk in postmenopausal women: the Iowa Women’s Health Study.

Vitamin D, a prosteroid hormone with anti-proliferative and pro-differentiation activity, is thought to act as a cancer chemopreventive agent. This study evaluated the association between vitamin D intake and breast cancer risk among women in a large prospective cohort study. A total of 34,321 postmenopausal women who had completed a questionnaire that included diet and supplement use were followed for breast cancer incidence from 1986 to 2004. Adjusted relative risks (RR) for breast cancer were calculated for dietary, supplemental, and total vitamin D intake among all women. The adjusted RR of breast cancer for women consuming >800 IU/day versus <400 IU/day total vitamin D was 0.89 (95% CI: 0.77-1.03). RRs were stronger among women with negative than positive ER or PR status. The association of high vitamin D intake with breast cancer was strongest in the first 5 years after baseline dietary assessment (RR = 0.66; 95% CI: 0.46-0.94 compared with lowest-intake group), and diminished over time. Changes in vitamin D intake over time might have contributed to the diminished association observed in later years. Vitamin D intake of >800 IU/day appears to be associated with a small decrease in risk of breast cancer among postmenopausal women. Studies evaluating all sources of vitamin D, especially sun exposure, are needed to fully understand the association between vitamin D and breast cancer risk.

Cancer Causes Control. 2007 Sep;18(7):775-82

Vitamin D and prevention of breast cancer: pooled analysis.

BACKGROUND: Inadequate photosynthesis or oral intake of Vitamin D are associated with high incidence and mortality rates of breast cancer in ecological and observational studies, but the dose-response relationship in individuals has not been adequately studied. METHODS: A literature search for all studies that reported risk by of breast cancer by quantiles of 25(OH)D identified two studies with 1,760 individuals. Data were pooled to assess the dose-response association between serum 25(OH)D and risk of breast cancer. RESULTS: The medians of the pooled quintiles of serum 25(OH)D were 6, 18, 29, 37, and 48 ng/ml. Pooled odds ratios for breast cancer from lowest to highest quintile, were 1.00, 0.90, 0.70, 0.70, and 0.50 (p trend<0.001). According to the pooled analysis, individuals with serum 25(OH)D of approximately 52 ng/ml had 50% lower risk of breast cancer than those with serum <13 ng/ml. This serum level corresponds to intake of 4,000 IU/day. This exceeds the National Academy of Sciences upper limit of 2,000 IU/day. A 25(OH)D level of 52 ng/ml could be maintained by intake of 2,000 IU/day and, when appropriate, about 12 min/day in the sun, equivalent to oral intake of 3,000 IU of Vitamin D(3). CONCLUSIONS: Intake of 2,000 IU/day of Vitamin D(3), and, when possible, very moderate exposure to sunlight, could raise serum 25(OH)D to 52 ng/ml, a level associated with reduction by 50% in incidence of breast cancer, according to observational studies.

J Steroid Biochem Mol Biol. 2007 Mar;103(3-5):708-11

(-)-Epigallocatechin-3-gallate downregulates estrogen receptor alpha function in MCF-7 breast carcinoma cells.

BACKGROUND: (-)-Epigalloca-techin-3-gallate (EGCG) is the most active catechin present in green tea, demonstrated to have chemopreventive action and to kill cancer cells selectively. As a previous study found that catechins could compete with 17-beta-estradiol for binding to estrogen receptor alpha (ERalpha), we asked whether EGCG could regulate ERalpha action. METHODS: We used MCF-7, a breast carcinoma cell line having a high level of ERalpha expression. The cells were treated with various EGCG concentrations and cell viability was evaluated by MTT assay. ERalpha and pS2 expression were analyzed by RT-PCR after RNA extraction. To better define EGCG action in relation to ERalpha, we studied EGCG cytotoxicity on MCF-7 resistant to tamoxifen (MCF-7tam), MCF-7 treated with 10(-7)M ICI 182,780 for 8 days and on MDA-MB-231, a cell line that lacked ERalpha by flow cytometry (FCM). RESULTS: Both ERalpha and pS2 mRNA were expressed in samples treated with low EGCG concentration (30 microg/ml). At this concentration, no cell change was detectable. In contrast, pS2 expression was lost in samples treated with 100 microg/ml EGCG for 24h, indicating ERalpha alteration. EGCG cytotoxicity was lower when ERalpha was not present (MDA-MB-231) or inactivated (by tamoxifen or ICI 182,780). CONCLUSIONS: Functionally active ERalpha may have a role in EGCG cytotoxicity, increasing the sensitivity to the drug. As higher EGCG concentrations also killed cells resistant to tamoxifen or treated by 10(-7)M ICI 182,780, EGCG ought to be better investigated in breast carcinoma cells treated with drugs targeted to steroid receptors, as a potential complement of therapy.

Cancer Detect Prev. 2007;31(6):499-504

Risk assessment for vitamin D.

The objective of this review was to apply the risk assessment methodology used by the Food and Nutrition Board (FNB) to derive a revised safe Tolerable Upper Intake Level (UL) for vitamin D. New data continue to emerge regarding the health benefits of vitamin D beyond its role in bone. The intakes associated with those benefits suggest a need for levels of supplementation, food fortification, or both that are higher than current levels. A prevailing concern exists, however, regarding the potential for toxicity related to excessive vitamin D intakes. The UL established by the FNB for vitamin D (50 microg, or 2,000 IU) is not based on current evidence and is viewed by many as being too restrictive, thus curtailing research, commercial development, and optimization of nutritional policy. Human clinical trial data published subsequent to the establishment of the FNB vitamin D UL published in 1997 support a significantly higher UL. We present a risk assessment based on relevant, well-designed human clinical trials of vitamin D. Collectively, the absence of toxicity in trials conducted in healthy adults that used vitamin D dose > or = 250 microg/d (10,000 IU vitamin D3) supports the confident selection of this value as the UL.

Am J Clin Nutr. 2007 Jan;85(1):6-18

Curcumin and cancer: An “old-age” disease with an “age-old” solution.

Cancer is primarily a disease of old age, and that life style plays a major role in the development of most cancers is now well recognized. While plant-based formulations have been used to treat cancer for centuries, current treatments usually involve poisonous mustard gas, chemotherapy, radiation, and targeted therapies. While traditional plant-derived medicines are safe, what are the active principles in them and how do they mediate their effects against cancer is perhaps best illustrated by curcumin, a derivative of turmeric used for centuries to treat a wide variety of inflammatory conditions. Curcumin is a diferuloylmethane derived from the Indian spice, turmeric (popularly called “curry powder”) that has been shown to interfere with multiple cell signaling pathways, including cell cycle (cyclin D1 and cyclin E), apoptosis (activation of caspases and down-regulation of antiapoptotic gene products), proliferation (HER-2, EGFR, and AP-1), survival (PI3K/AKT pathway), invasion (MMP-9 and adhesion molecules), angiogenesis (VEGF), metastasis (CXCR-4) and inflammation (NF-kappaB, TNF, IL-6, IL-1, COX-2, and 5-LOX). The activity of curcumin reported against leukemia and lymphoma, gastrointestinal cancers, genitourinary cancers, breast cancer, ovarian cancer, head and neck squamous cell carcinoma, lung cancer, melanoma, neurological cancers, and sarcoma reflects its ability to affect multiple targets. Thus an “old-age” disease such as cancer requires an “age-old” treatment.

Cancer Lett. 2008 Aug 18;267(1):133-64