Vitamin D and breast cancer: Past and present

Abstract

The presence of the vitamin D receptor in mammary gland and breast cancer has been recognized since the early 1980s, and multiple pre-clinical studies have demonstrated that its ligand 1,25D modulates normal mammary gland development and sensitivity to carcinogenesis. Although studies have characterized many 1,25D responsive targets in normal mammary cells and in breast cancers, validation of relevant targets that regulate cell cycle, apoptosis, autophagy and differentiation, particularly in vivo, has been challenging. 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. 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, analysis of VDR actions in specific molecular subtypes of the disease is necessary to clarify the conflicting data. Genomic, proteomic and metabolomic analyses of in vitro and in vivo model systems is also warranted to comprehensively understand the network of vitamin D regulated pathways in the context of breast cancer heterogeneity.

Keywords: Breast cancer; Mammary gland; VDR; Vitamin D.

Figure 1. Model depicting VDR expression during mammary stem cell lineage determination

Mammary stem cells are capable of asymmetric division which generates daughter stem cells and transit amplifying cells. The transit amplifying cells proliferate slowly and give rise to non-cycling progenitor cells, the earliest cell type in this hierarchy that has been demonstrated to express VDR. This cell population (or a slightly later VDR positive progenitor cell) also expresses CYP24A1. Both basal and luminal cell populations originate from the VDR positive progenitor cell. In the course of basal cell differentiation VDR expression is silenced. During luminal cell differentiation both VDR positive and VDR negative cells arise. Eleven luminal cell populations have been identified based on expression of cytokeratins and hormone receptors (ER, AR, VDR). Five of the eleven luminal cell populations express VDR. Any of the cell populations shown here could theoretically give rise to breast cancer, leading to extraordinary heterogeneity in VDR expression. Schematic is based on data from refs –; see text for additional details.