Abstract A117: Vitamin D, parathyroid hormone, Cyp2r1, and breast cancer susceptibility in mice

Abstract

Abstract Vitamin D is a group of fat-soluble secosteroids. Apart from its main physiological role in calcium homeostasis, several studies have demonstrated a wide range of functions of vitamin D which can be associated with cancer. Even though the exact mechanism underlying the protective action of vitamin D against cancer is not clearly understood, there is strong experimental evidence showing that vitamin D participates in cell growth regulation, apoptosis and proliferation in normal and malignant breast cells. This evidence has lead to the hypothesis that high levels of vitamin D might reduce the risk of breast cancer. In order to be biologically active, vitamin D must be converted to its active form 1,25(OH)2D3. CYP2R1 is a major vitamin D hydroxylase that catalyzes the first step of this activation producing 25(OH)D3. Cyp2r1 is located within the SuprMam1 locus, a mammary tumour susceptibility locus identified in the BALB/c-Trp53+/- mouse model of spontaneous breast cancer (1). Affymetrix data comparing T cell gene expression have identified Cyp2r1 to be differentially expressed between BALB/c and C57BL/6 mouse strains (0.68 fold reduction in BALB/c, the mammary tumour susceptible strain). As lower CYP2R1 levels should result in lower vitamin D levels and may contribute to the higher cancer susceptibility of BALB/c mice, we studied the Cyp2r1 gene expression and plasma 25(OH)D3 levels in SM09 congenic-mice (BALB/c SuprMam loci in C57BL/6 background) in comparison to C57BL/6-controls. A real-time quantitative PCR of Cyp2r1 in different tissues from SM09 and control mice revealed that there is a significant difference in Cyp2r1 expression in mammary glands of the two strains (2.76 fold reduction in SM09, p=0.04). But this difference was not observed in liver or lymph node tissues of the same mice. Further investigation of the major regulators of vitamin D pathway found that differences in plasma 25(OH)D3 levels were not reliably detected, and there was no difference in plasma phosphate or calcium levels between the congenic and control mouse strains. However, 3-fold higher levels of parathyroid hormone (Pth) were measured in female mice carrying the BALB/c allele of the SuprMam1 locus. Further, expression profiling of the major genes involved in the vitamin D pathway by affymetrix exon array on mammary glands from SM09 and control mice indicated many were differentially expressed, indicating disruption of the vitamin D pathway. Further investigations are underway to determine if genetic differences in the Pth or Cyp2R1 gene are responsible for this disruption, and if this is of biological significance for tumour growth in vivo. 1. Blackburn AC, Hill LZ, Roberts AL, et al. Genetic mapping in mice identifies DMBT1 as a candidate modifier of mammary tumors and breast cancer risk. Am J Pathol. 2007; 170:2030–41. Citation Format: Madara Ratnadiwakara, Rohan B. Williams, Anneke C. Blackburn. Vitamin D, parathyroid hormone, Cyp2r1, and breast cancer susceptibility in mice. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A117.