The SuprMam1 breast cancer susceptibility locus disrupts the vitamin D/ calcium/ parathyroid hormone pathway and alters bone structure in congenic mice

Abstract

Breast cancer is a complex disease, and approximately 30% of cases are considered to be hereditary or familial, with a large fraction of this being polygenic. However, it is difficult to demonstrate the functional importance of genes of small effect in population studies, and these genes are not always easily targeted for prevention. The SuprMam (suppressor of mammary tumour) breast cancer susceptibility alleles were previously identified as contributors to spontaneous mammary tumour development in Trp53+/− mice. In this study, we have generated and characterised congenic mice that contain the BALB/c SuprMam1 (susceptibility) locus on a C57BL/6 (resistant) background and discovered a subtle impairment in the vitamin D/ calcium/ parathyroid hormone (PTH) pathway. This was evident as altered gene expression in the mammary glands of key players in this pathway. Further functional analysis of the mice revealed elevated PTH levels, reduced Cyp27b1 expression in kidneys, and reduced trabecular bone volume/ tissue volume percentage. Plasma 25(OH)D and serum calcium were unchanged. This impairment was a result of genetic differences and occurred only in females, but the elevated PTH levels could be overcome with either calcium or vitamin D dietary supplementation. Either low levels of active vitamin D (1,25(OH)2D) or chronically elevated PTH levels may contribute to increased breast cancer susceptibility. These indicators are not easily measured in human population studies, but either mechanism may be preventable with dietary calcium or vitamin D supplements. Therefore, SuprMam congenic mice could serve as a valuable model for studying the role of gene-hormone-environment interactions of the vitamin D/ calcium/ PTH pathway in cancer and other diseases and for testing preventive interventions.