The anti-proliferative effects of 1α,25(OH)2D3 on breast and prostate cancer cells are associated with induction of BRCA1 gene expression

Campbell, Moray J.; Gombart, Adrian F.; Kwok, Scott H.; Park, S; Koeffler, H. Phillip

doi:10.1038/sj.onc.1203888

Cited by 96 publications

(76 citation statements)

References 39 publications

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“…In support, frequently elevated co-repressor mRNA expression has been found, most commonly involving NCoR2/SMRT, in malignant prostate primary cultures and cell lines, with reduced 1a,25(OH) 2 D 3 anti-proliferative response (81,87,169,174) . These data indicate that the VDR: corepressor maybe critical in determining 1a,25(OH) 2 D 3 responsiveness in cancer cells.…”

Section: Epigenetic Resistancementioning

confidence: 92%

The vitamin D receptor in cancer

2008

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Over the last 25 years roles have been established for vitamin D receptor (VDR) in influencing cell proliferation and differentiation. For example, murine knock-out approaches have revealed a role for the VDR in controlling mammary gland growth and function. These actions appear widespread, as the enzymes responsible for 1a,25-dihydroxycholecalciferol generation and degradation, and the VDR itself, are all functionally present in a wide range of epithelial and haematopoietic cell types. These findings, combined with epidemiological and functional data, support the concept that local, autocrine and paracrine VDR signalling exerts control over cell-fate decisions in multiple cell types. Furthermore, the recent identification of bile acid lithocholic acid as a VDR ligand underscores the environmental sensing role for the VDR. In vitro and in vivo dissection of VDR signalling in cancers (e.g. breast, prostate and colon) supports a role for targeting the VDR in either chemoprevention or chemotherapy settings. As with other potential therapeutics, it has become clear that cancer cells display de novo and acquired genetic and epigenetic mechanisms of resistance to these actions. Consequently, a range of experimental and clinical options are being developed to bring about more targeted actions, overcome resistance and enhance the efficacy of VDR-centred therapeutics. The cancer burdenThe impact of cancer continues to be one of the greatest burdens in the developed world and is also increasingly impacting on the developing world. Approximately 1 . 5 million individuals will die from breast, colon or prostate cancer this year, and the total number of deaths from cancer accounts for 13 % of all deaths worldwide and for one in every four deaths in the UK and USA (1) . The impact is also economic; $280 · 10 9 is spent annually worldwide on the treatment of patients. Many cancers are however preventable, and through lifestyle choices such as smoking, diet and exercise the worldwide incidence of cancer could be cut by 40 % (2,3) . Major risk factors for cancer DietRecently, the appreciation of the impact of diet on cancer has come to the fore, with a number of studies establishing unequivocal relationships between diet and cancer initiation and progression. Reflecting the accumulation of these data, the WHO has now stated that diet forms the secondmost preventable cause of cancer (after smoking) (3) . This impact will rise further as a result of demographic factors, and quite possibly because of changing dietary habits worldwide, which will contribute further to the projected increase in cancer incidence in developing nations. Highprofile malignancies such as breast, prostate, and colon cancer typify this scenario, in which the aetiology of the disease reflects the cumulative impact of dietary factors over an individual's lifetime (4)(5)(6) . The relationship between diet and disease is already exploited clinically, e.g. in the Selenium and Vitamin E Cancer Prevention Trial to assess the chemoprevention potential of vitamin E ...

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Section: Epigenetic Resistancementioning

confidence: 92%

The vitamin D receptor in cancer

2008

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“…Parallel studies by ourselves and others have found epidemiologic links between the incidence of breast cancers and low serum 25(OH)D 3 levels (13,14); the risk is compounded by specific VDR polymorphisms (15,16). In vitro studies show that MDA-MB-231 and other cancer cells show a spectrum of insensitivity toward 1a,25(OH) 2 D 3 (17,18). Taken together, these data suggest that functional VDR-mediated signaling is required for correct gland function and that 1a,25(OH) 2 D 3 -deficient environments and/or cellular mechanisms which suppress sensitivity to 1a,25(OH) 2 D 3 are both associated with malignancy.…”

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confidence: 87%

“…Cells were seeded at low and high densities (2 Â 10 , respectively) and either harvested after 24 hours (subconfluent) or cultured until the highdensity cultures reached confluency (72 hours) to give subconfluent and confluent cultures, respectively. Whole-cell lysates were prepared at indicated time points and Western immunoblot analysis was done as previously described (17). Briefly, 30 Ag of total protein for each sample were electrophoresed on an SDS-polyacrylamide gel, transferred onto polyvinylidene difluoride membrane (Immobilon-P, Millipore, Bedford, MA), and blocked with TBS-Tween 20 containing 5% milk powder for 1 hour.…”

Section: Methodsmentioning

confidence: 99%

“…Taken together, these data suggest that functional VDR-mediated signaling is required for correct gland function and that 1a,25(OH) 2 D 3 -deficient environments and/or cellular mechanisms which suppress sensitivity to 1a,25(OH) 2 D 3 are both associated with malignancy. The mechanisms for cellular 1a,25(OH) 2 D 3 insensitivity in breast cancer are as yet unclear and limit therapeutic applications, although a lack of a functional VDR alone cannot explain resistance (17,19).…”

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confidence: 99%

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Altered Nuclear Receptor Corepressor Expression Attenuates Vitamin D Receptor Signaling in Breast Cancer Cells

Banwell¹,

MacCartney²,

Guy

et al. 2006

Clinical Cancer Research

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Purpose:We hypothesized that deregulated corepressor actions, with associated histone deacetylation activity, epigenetically suppressed vitamin D receptor (VDR) responsiveness and drives resistance towards 1a,25-dihydroxyvitamin D 3 . Experimental Design: Profiling, transcriptional, and proliferation assays were undertaken in 1a,25(OH) 2 D 3 -sensitive MCF-12A nonmalignant breast epithelial cells, a panel of breast cancer cell lines, and a cohort of primary breast cancer tumors (n = 21). Results: Elevated NCoR1 mRNA levels correlated with suppressed regulation of VDR target genes and the ability of cells to undergo arrest in G 1 of the cell cycle. A similar increased ratio of corepressor mRNA to VDR occurred in matched primary tumor and normal cells, noticeably in estrogen receptor a^negative (n = 7) tumors. 1a,25(OH) 2 D 3 resistance in cancer cell lines was targeted by cotreatments with either 1a,25(OH) 2 D 3 or a metabolically stable analogue (RO-26-2198) in combination with either trichostatin A (TSA; histone deacetylation inhibitor) or 5-aza-2V-deoxycytidine (DNA methyltransferase inhibitor). Combinations of vitamin D 3 compounds with TSA restored VDR antiproliferative signaling (target gene regulation, cell cycle arrest, and antiproliferative effects in liquid culture) to levels which were indistinguishable from MCF-12A cells. Conclusions: Increased NCoR1 mRNA is a novel molecular lesion in breast cancer cells, which acts to suppress responsiveness of VDR target genes, resulting in 1a,25(OH) 2 D 3 resistance and seems to be particularly associated with estrogen receptor negativity.This lesion provides a novel molecular diagnostic and can be targeted by combinations of vitamin D 3 compounds and low doses of TSA.The nuclear receptor superfamily regulates diverse signals that are central to the formation and homeostasis of the mammary gland. The postgenomic description of the superfamily conjoined with profiling approaches (1) reveals that breast myoepithelial and epithelial cells express a rich cohort of nuclear receptors, many of which display overt nutrient-sensing capacity for micronutrients and macronutrients alongside the estrogen receptors (ERa and ERh; refs. 2 -6).Several of the diet-sensing nuclear receptors, such as the VDR, preferentially form heterodimers with retinoid X receptors whereas the ERs preferentially heterodimerize with one another. For the nuclear receptors to regulate transcriptional programs, these dimers must be contained as subunits in either large gene coactivator or corepressor complexes. In the absence of ligand, receptors exist in an apo state as part of large complexes (f2.0 MDa; ref. 7), associated with corepressors (e.g., NCoR1, NCoR2/SMRT, and TRIP15/Alien), and bound to response element sequences. These complexes actively recruit a range of enzymes that posttranslationally modify histone tails (e.g., histone deacetylases and methyltransferases) and thereby maintain a locally closed chromatin structure around response element sequences (8). Ligand binding induces a...

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“…Treatment of breast and prostate cancer cells with 1a,25-dihydroxyvitamin D3 induced BRCA1 expression through the vitamin D receptor, a mechanism that may contribute to vitamin D receptor mediated growth arrest and apoptosis (Campbell et al, 2000). BRCA1 may also be regulated separately at the protein level (Blagosklonny et al, 1999;Ma et al, 2003).…”

Section: Regulation Of Brca1 Expressionmentioning

confidence: 99%

BRCA1 gene in breast cancer

Rosen

Fan

Pestell

et al. 2003

Journal Cellular Physiology

242

195

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The BRCA1 gene was identified and cloned in 1994 based on its linkage to early onset breast cancer and breast-ovarian cancer syndromes in women. While inherited mutations of BRCA1 are responsible for about 40-45% of hereditary breast cancers, these mutations account for only 2-3% of all breast cancers, since the BRCA1 gene is rarely mutated in sporadic breast cancers. However, BRCA1 expression is frequently reduced or absent in sporadic cancers, suggesting a much wider role in mammary carcinogenesis. Since BRCA1 was cloned in 1994, its molecular function has been the subject of intense investigation. These studies have revealed multiple functions of the BRCA1 that may contribute to its tumor suppressor activity, including roles in: cell cycle progression, several highly specialized DNA repair processes, DNA damage-responsive cell cycle checkpoints, regulation of a set of specific transcriptional pathways, and apoptosis. Many of these functions are linked to protein:protein interactions involving different portions of the 1,863 amino acid (aa) BRCA1 protein. BRCA1 functions in cell cycle progression and the DNA damage response appear to be regulated by distinct and specific phosphorylation events, but the molecular pathways activated by these phosphorylations are only beginning to be unraveled. In addition, the reason that BRCA1 mutation carriers develop specific tumor types (breast and ovarian cancers in women and possibly prostate cancers in men) is not clearly understood. Elucidation of the precise molecular functions of the BRCA1 gene product will greatly enhance our understanding of the pathogenesis of hereditary as well as sporadic mammary carcinogenesis.

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The anti-proliferative effects of 1α,25(OH)2D3 on breast and prostate cancer cells are associated with induction of BRCA1 gene expression

Cited by 96 publications

References 39 publications

The vitamin D receptor in cancer

The vitamin D receptor in cancer

Altered Nuclear Receptor Corepressor Expression Attenuates Vitamin D Receptor Signaling in Breast Cancer Cells

BRCA1 gene in breast cancer

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