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Altered Nuclear Receptor Corepressor Expression Attenuates Vitamin D Receptor Signaling in Breast Cancer Cells

Authors' Affiliations: ¹ Institute of Biomedical Research, Endocrinology and Metabolism and ² Division of Immunity and Infection, University of Birmingham Medical School, Edgbaston, Birmingham, United Kingdom; ³ Hoffman La Roche, Nutley, New Jersey; and ⁴ Department of Clinical Biochemistry, St. George's Hospital Medical School, London, United Kingdom

Requests for reprints: Moray J. Campbell, Institute of Biomedical Research, Endocrinology and Metabolism, University of Birmingham Medical School, Wolfson Drive, Edgbaston, Birmingham, United Kingdom. Phone: 44-121-415-8713; Fax: 011-44-121-415-8712; E-mail: m.j.campbell{at}bham.ac.uk.

Purpose: We hypothesized that deregulated corepressor actions, with associated histone deacetylation activity, epigenetically suppressed vitamin D receptor (VDR) responsiveness and drives resistance towards 1,25-dihydroxyvitamin D₃.

Experimental Design: Profiling, transcriptional, and proliferation assays were undertaken in 1,25(OH)₂D₃-sensitive MCF-12A nonmalignant breast epithelial cells, a panel of breast cancer cell lines, and a cohort of primary breast cancer tumors (n = 21).

Results: Elevated NCoR1 mRNA levels correlated with suppressed regulation of VDR target genes and the ability of cells to undergo arrest in G₁ of the cell cycle. A similar increased ratio of corepressor mRNA to VDR occurred in matched primary tumor and normal cells, noticeably in estrogen receptor –negative (n = 7) tumors. 1,25(OH)₂D₃ resistance in cancer cell lines was targeted by cotreatments with either 1,25(OH)₂D₃ or a metabolically stable analogue (RO-26-2198) in combination with either trichostatin A (TSA; histone deacetylation inhibitor) or 5-aza-2'-deoxycytidine (DNA methyltransferase inhibitor). Combinations of vitamin D₃ compounds with TSA restored VDR antiproliferative signaling (target gene regulation, cell cycle arrest, and antiproliferative effects in liquid culture) to levels which were indistinguishable from MCF-12A cells.

Conclusions: Increased NCoR1 mRNA is a novel molecular lesion in breast cancer cells, which acts to suppress responsiveness of VDR target genes, resulting in 1,25(OH)₂D₃ resistance and seems to be particularly associated with estrogen receptor negativity. This lesion provides a novel molecular diagnostic and can be targeted by combinations of vitamin D₃ compounds and low doses of TSA.

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