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Altered nuclear receptor corepressor expression attenuates vitamin D receptor signaling in breast cancer cells

Claire M Banwell1, Donia P MacCartney, Michelle Guy

  • 1Institute of Biomedical Research, Endocrinology and Metabolism and Division of Immunity and Infection, University of Birmingham Medical School, Edgbaston, Birmingham, United Kingdom.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|April 13, 2006
PubMed
Abstract

Insights

Increased NCoR1 mRNA in breast cancer suppresses vitamin D receptor (VDR) function, leading to drug resistance. Combining vitamin D compounds with histone deacetylase inhibitors like TSA can restore VDR activity.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Epigenetics

Background:

  • Vitamin D receptor (VDR) plays a role in cell growth and differentiation.
  • VDR signaling is often impaired in breast cancer, contributing to disease progression.
  • Corepressors can epigenetically regulate gene expression, potentially impacting VDR activity.

Purpose of the Study:

  • To investigate the role of corepressors, specifically NCoR1, in VDR responsiveness in breast cancer.
  • To determine if NCoR1-mediated suppression of VDR contributes to resistance to 1alpha,25-dihydroxyvitamin D(3) (1,25(OH)2D3).
  • To explore therapeutic strategies targeting NCoR1-mediated VDR resistance.

Main Methods:

  • Gene expression profiling and transcriptional assays in breast epithelial cells and cancer cell lines.
  • Analysis of primary breast cancer tumors (n=21) for NCoR1 and VDR levels.
  • In vitro experiments testing combinations of 1,25(OH)2D3 (or analogue RO-26-2198) with epigenetic modifiers (TSA, 5-aza-2'-deoxycytidine).

Main Results:

  • Elevated NCoR1 mRNA levels correlated with suppressed VDR target gene regulation and cell cycle arrest.
  • A higher ratio of corepressor to VDR mRNA was observed in primary tumors, particularly in estrogen receptor alpha-negative (ERα-) cases.
  • Combination therapy with 1,25(OH)2D3 and trichostatin A (TSA) restored VDR antiproliferative signaling in resistant cancer cells.

Conclusions:

  • Increased NCoR1 mRNA is a novel molecular lesion in breast cancer, causing VDR target gene suppression and 1,25(OH)2D3 resistance.
  • This NCoR1-mediated resistance is associated with ERα-negative breast cancer.
  • The combination of vitamin D compounds and low-dose TSA represents a potential therapeutic strategy for overcoming VDR resistance.

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