Abstract B36: Development of calcitrol-resistance in triple-negative breast cancer cells through SLUG-mediated coordinate repression of CYP2R1, CYP27B1, and VDR gene promoters

Abstract

Abstract Metastatic breast and other cancers are often found to be refractory to vitamin D therapy. Vitamin D is synthesized from 7-dehydrocholesterol, an intermediate metaboltie in cholesterol synthesis. Ultraviolet irradiation in sunlight-exposed skin induces a photochemical reaction of 7–25-position by vitamin D 25-hydroxylase (CYP2R1), to yield 25-hydroxyvitamin D3 (cholecalciferol). Vitamin D3 is hydroxylated at the 25-position by vitamin D 25-hydroxylase (CYP2R1), to yield 25-hydroxyvitamin D3 (25(OH)D3; 25-hydroxycholecalciferol), the major form of vitamin D in the circulation. 25(OH)D3 is further hydroxylated at the 1 -position by the 25-hydroxyvitamin D 1 -hydroxylase (CYP27B1) to produce calcitrol (VD3). VD3 exhibits physiological and pharmacological effects by binding to the vitamin D receptor (VDR), a transcription factor of the nuclear receptor superfamily. Although photoactivated cholecalciferol is mainly hydroxylated in the liver and kidney, many other cells including breast cells have significant expressions of CYP2R1, CYP27B1 and VDR. Breast cells thus should be able to activate and utilize cholecalciferol if these proteins are not suppressed. We report here that the metastasis modulator protein SLUG, which is often overexpressed in metastatic triple negative breast cancer cells, coordinately repressse the levels of CYP2R1, CYP27B1 and VDR proteins in the breast cancer cells to induce vitamin D-resistance in these cells. SLUG inhibited CYP2R1, CYP27B1 and VDR gene promoter activities in these cells. ChIP assays revealed that SLUG is recruited at the CYP2R1, CYP27B1 and VDR gene promoters. Knockdown of SLUG in highly invasive MDA-MB-231 and BT549 cells increased their CYP2R1, CYP27B1 and VDR gene expression and decreased their resistance their resistance to VD3 in vitro. Our data established that SLUG regulates vitamin D metabolism and contributes to the induction of VD3-resistance in human breast cancer cells through the inhibition of CYP2R1, CYP27B1 and VDR gene promoters epigenetically through chromatin remodeling. Supported in parts by the DOD-CDMRP grants BC050641 and BC103645. Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B36.