The impact of vitamin D in breast cancer: genomics, pathways, metabolism

Abstract

Nuclear receptors exert profound effects on mammary gland physiology and have complex roles in the etiology of breast cancer. In addition to receptors for classic steroid hormones such as estrogen and progesterone, the nuclear vitamin D receptor (VDR) interacts with its ligand 1α,25(OH)2D3 to modulate the normal mammary epithelial cell genome and subsequent phenotype. Observational studies suggest that vitamin D deficiency is common in breast cancer patients and that low vitamin D status enhances the risk for disease development or progression. Genomic profiling has characterized many 1α,25(OH)2D3 responsive targets in normal mammary cells and in breast cancers, providing insight into the molecular actions of 1α,25(OH)2D3 and the VDR in regulation of cell cycle, apoptosis, and differentiation. New areas of emphasis include regulation of tumor metabolism and innate immune responses. However, the role of VDR in individual cell types (i.e., epithelial, adipose, fibroblast, endothelial, immune) of normal and tumor tissues remains to be clarified. Furthermore, the mechanisms by which VDR integrates signaling between diverse cell types and controls soluble signals and paracrine pathways in the tissue/tumor microenvironment remain to be defined. Model systems of carcinogenesis have provided evidence that both VDR expression and 1α,25(OH)2D3 actions change with transformation but clinical data regarding vitamin D responsiveness of established tumors is limited and inconclusive. Because breast cancer is heterogeneous, analysis of VDR actions in specific molecular subtypes of the disease may help to clarify the conflicting data. The expanded use of genomic, proteomic and metabolomic approaches on a diverse array of in vitro and in vivo model systems is clearly warranted to comprehensively understand the network of vitamin D regulated pathways in the context of breast cancer.

Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects

“…Also in colorectal cancer, increased CYP24A1 gene copy number is shown, whereas no differences in CYP24A1 promoter methylation are seen (189). In agreement with these findings, 10 -13% of human breast cancers in the dataset from The Cancer Genome Atlas show altered CYP24A1 expression, most often due to gene amplification and characterized by enhanced mRNA levels (323). Of note, high CYP24A1 expression significantly correlates with poor survival in lung cancer cohorts (50).…”

“…Recently, Narvaez et al (323) reported that in The Cancer Genome Atlas datasets Ͻ2% of breast cancers exhibit genomic alterations (including amplifications, deletions, mutations, and changes in mRNA) (323). Nonetheless, multiple studies reported that in human cancer biopsies CYP27B1 mRNA expression (32, 47) and CYP27B1 protein levels (93,272,299) tend to be higher in well-differentiated tumors, whereas they are lower in more malignant and poorly differentiated tumors.…”

“…The presence of the VDR in tumor cells is a prerequisite for the antineoplastic effects of 1,25(OH) 2 D 3 . In most tumors, VDR expression is retained and, according to Narvaez et al (323), alterations in the VDR gene are only seen in 5% of cancers in The Cancer Genome atlas. Several studies suggested that enhanced tumor VDR expression levels are correlated with a better prognosis and prolonged overall survival (119,186).…”

“…SLCA1 encodes a plasma membrane glutamate transporter that is induced by 1,25(OH) 2 D 3 , whereas GLUL, which encodes glutamine synthetase, is repressed by 1,25(OH) 2 D 3 . These changes are accompanied by an accumulation of glutathione and changes in respiratory capacity, suggesting that 1,25(OH) 2 D 3 leads to a metabolic switch that might induce quiescence in mammary epithelial cells (323). F) REGULATION OF MICRORNAS BY 1,25(OH) 2 D 3 .…”

Nuclear receptor gene polymorphisms and warfarin dose requirements in the Quebec Warfarin Cohort

“…Molecular-based epidemiological studies have identified several functional polymorphisms in the VDR [21] and have demonstrated that the variants can affect the function of the receptor by altering its affinity to vitamin D [28,29]. VDR genetic variants have previously been associated with a number of diseases including pulmonary tuberculosis, diabetes, osteoporosis, asthma, ulcerative colitis, breast and female reproductive cancers, melanoma, systemic lupus erythematous and rheumatoid arthritis, Parkinson's disease, and coronary artery disease [30][31][32][33][34][35][36][37][38][39]. Pharmacogenetic studies have shown that VDR polymorphisms can modulate the response to a number of drugs including anti-tubercular and anti-psoriatic medications, anti-osteoporotic agents in postmenopausal women, interferon and ribavirin in patients with hepatitis C, vitamin D supplementation, and calcitriol [40][41][42][43][44][45][46], as well as with statin-induced myopathy [47].…”