Vitamin D and Breast Cancer: Mechanistic Update

Abstract

The presence of the vitamin D receptor (VDR) in mammary gland and breast cancer has long been recognized, and multiple preclinical studies have demonstrated that its ligand, 1,25-dihydroxyvitamin D (1,25D), modulates normal mammary gland development and inhibits growth of breast tumors in animal models. Vitamin D deficiency is common in breast cancer patients, and some evidence suggests that low vitamin D status enhances the risk for disease development or progression. Although many 1,25Dresponsive targets in normal mammary cells and in breast cancers have been identified, validation of specific targets that regulate cell cycle, apoptosis, autophagy, and differentiation, particularly in vivo, has been challenging. Model systems of carcinogenesis have provided evidence that both VDR expression and 1,25D actions change with transformation, but clinical data regarding vitamin D responsiveness of established tumors is limited and inconclusive. Because breast cancer is heterogeneous, the relevant VDR targets and potential sensitivity to vitamin D repletion or supplementation will likely differ between patient populations. Detailed analysis of VDR actions in specific molecular subtypes of the disease will be necessary to clarify the conflicting data. Genomic, proteomic, and metabolomic analyses of in vitro and in vivo model systems are also warranted to comprehensively understand the network of vitamin D-regulated pathways in the context of breast cancer heterogeneity. This review provides an update on recent studies spanning the spectrum of mechanistic (cell/molecular), preclinical (animal models), and translational work on the role of vitamin D in breast cancer.

Vitamin D and Cancer: An Historical Overview of the Epidemiology and Mechanisms

“…In colon carcinoma cells, 1,25-(OH) 2 D 3 upregulates an array of intercellular adhesion molecules that are constituents of adherens junctions and tight junctions, including E-cadherin, occludin, claudin-2 and -12, and ZO-1 and -2 [ 125 , 131 ]. As mentioned by JoEllen Welsh in an excellent recent review [ 187 ], breast cancer heterogeneity is reflected in available model systems of this disease, including human breast cancer cell lines. These differ in the expression of VDR and other hormone receptors and in their global gene expression profile and phenotype.…”

“…This in vivo action is difficult to dissect and probably results from a variable combination of mechanisms in the distinct systems that were assayed, including the inhibition of tumor cell growth, EMT, invasiveness, angiogenesis, and metastasis. Importantly, as occurs in cultured cancer cells, vitamin D antitumor action is mostly independent of TP53 gene status [ 119 , 187 ].…”

Endothelium-Dependent Induction of Vasculogenic Mimicry in Human Triple-Negative Breast Cancer Cells Is Inhibited by Calcitriol and Curcumin

“…On the other hand, calcitriol, the most active vitamin D metabolite, exerts pro-differentiating and antiproliferative effects in breast cancer [ 14 ], and has shown an anti-EMT effect in epithelial cells through inhibiting the PI3K/Akt/β-catenin pathway [ 15 ]. Also, calcitriol exerts potent anti-inflammatory activity, partially through downregulating JAK-STAT pathway activation and inflammatory cytokine production, processes known to be involved in carcinogenesis and VM [ 16 , 17 ]; however, calcitriol’s effects upon VM has not been explored.…”

Prevalence and Relevance of Vitamin D Deficiency in Newly Diagnosed Breast Cancer Patients: A Pilot Study

“…Some studies suggest that higher vitamin D levels might reduce the risk of developing breast cancer [ 14 , 27 , 28 , 29 , 30 ]. Animal studies have also shown that vitamin D deficiency might play a role in primary tumor growth and the development of metastases in breast cancer cells [ 31 ], and an association between low vitamin D receptor expression and occurrence of more aggressive breast cancer has been seen [ 32 ].…”