Function of the vitamin D endocrine system in mammary gland and breast cancer

Abstract

The nuclear receptor for 1α,25-dihydroxycholecalciferol (1,25D), the active form of vitamin D, has anti-tumor actions in many tissues. The vitamin D receptor (VDR) is expressed in normal mammary gland and in many human breast cancers suggesting it may represent an important tumor suppressor gene in this tissue. When activated by 1,25D, VDR modulates multiple cellular pathways including those related to energy metabolism, terminal differentiation and inflammation. There is compelling pre-clinical evidence that alterations in vitamin D status affect breast cancer development and progression, while clinical and epidemiological data are suggestive but not entirely consistent. The demonstration that breast cells express CYP27B1 (which converts the precursor vitamin D metabolite 25D to the active metabolite 1,25D) and CYP24A1 (which degrades both 25D and 1,25D) provides insight into the difficulties inherent in using dietary vitamin D, sun exposure and/or serum biomarkers of vitamin D status to predict disease outcomes. Emerging evidence suggests that the normally tight balance between CYP27B1 and CYP24A1 becomes deregulated during cancer development, leading to abrogation of the tumor suppressive effects triggered by VDR. Research aimed at understanding the mechanisms that govern uptake, storage, metabolism and actions of vitamin D steroids in normal and neoplastic breast tissue remain an urgent priority.

Keywords: Breast cancer; CYP24A1; CYP27B1; Mammary gland; Metabolism; VDR; Vitamin D.

Figure 1. Analysis of genomic alterations in VDR, CYP24A1 and CYP27B1 in human breast tumors

This oncoprint reports cases in which the indicated alterations (amplification, deep deletion, mRNA upregulation or mRNA downregulation) in VDR, CYP24A1 or CYP27B1 were detected in individual tumor samples. The TGCA dataset utilized was the Breast Cancer (METABRIC) consisting of 2509 patients. Data analysis was conducted within the cBIOPortal for Cancer Genomics at http://www.cbioportal.org/.