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DNA methylation-related vitamin D receptor insensitivity in breast cancer

Radharani Marik1, Maryjo Fackler, Edward Gabrielson

  • 1Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Cancer Biology & Therapy
|May 1, 2010
PubMed

Insights

Breast cancer cells resist Calcitriol due to epigenetic silencing of the vitamin D receptor (VDR) via promoter hypermethylation. Reversing this VDR methylation may restore sensitivity to Calcitriol-based differentiation therapy.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Cancer Research

Background:

  • Calcitriol (1α, 25(OH)(2)-Vitamin D3) regulates normal mammary gland differentiation via the vitamin D receptor (VDR).
  • Breast cancer cells often exhibit resistance to Calcitriol, hindering its therapeutic potential.
  • Epigenetic modifications, specifically promoter hypermethylation, are implicated in VDR silencing.

Purpose of the Study:

  • To investigate the mechanism of Calcitriol resistance in breast cancer.
  • To explore the role of VDR promoter hypermethylation in VDR silencing.
  • To assess the potential of reversing VDR methylation for restoring Calcitriol sensitivity.

Main Methods:

  • Bisulfite sequencing to analyze VDR promoter methylation.
  • 5'deoxy-azacytidine (AZA) treatment to demethylate VDR promoter.
  • Quantitative methylation-specific PCR to assess methylation in tumors and normal tissue.
  • Analysis of VDR mRNA transcript length and expression of VDR-responsive genes.

Main Results:

  • VDR promoter hypermethylation was identified upstream and near the transcription start site in breast cancer cells.
  • AZA treatment demethylated VDR CpG islands, increasing VDR mRNA levels.
  • Primary breast tumors showed hypermethylation, unlike normal breast tissue.
  • Breast cancers predominantly expressed 5'-truncated VDR transcripts, while normal tissue expressed full-length VDR.
  • Expression of VDR-responsive genes (e.g., p21) was reduced in breast cancers.
  • AZA treatment restored full-length VDR expression and increased expression of VDRE-containing genes.

Conclusions:

  • Promoter methylation-mediated silencing of functional VDR variants contributes to Calcitriol insensitivity in breast cancer.
  • Reduced expression of downstream VDR pathway effectors is linked to VDR silencing.
  • Pharmacological reversal of VDR methylation may re-sensitize breast cancer cells to Calcitriol differentiation therapy.

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