Unmasking of epigenetically silenced genes reveals DNA promoter methylation and reduced expression of PTCH in breast cancer

Ido Wolf, Shikha Bose, Julian C. Desmond, Bryan T. Lin, Elizabeth A. Williamson, Beth Y. Karlan, H. Phillip Koeffler

Research output: Contribution to journalArticlepeer-review

81 Scopus citations

Abstract

A pharmacological-based global screen for epigenetically silenced tumor suppressor genes was performed in MCF-7 and MDA-MB-231 breast cancer cells. Eighty-one genes in MCF-7 cells and 131 in MDA-MB-231 cells were identified, that had low basal expression and were significantly upregulated following treatment. Eighteen genes were studied for methylation and/or expression in breast cancer; PTCH, the receptor for the hedgehog (Hh) pathway and a known tumor suppressor gene, was selected for further analysis. Methylation of the PTCH promoter was found in MCF-7 cells and in breast cancer samples, and correlated with low PTCH expression. Immunohistochemical analysis of breast tissue arrays revealed high expression of PTCH in normal breast compared to ductal carcinomas in situ (DCIS) and invasive ductal carcinomas; furthermore, association was found between PTCH expression and favorable prognostic factors. PTCH is an inhibitor of the Hh pathway, and its silencing activates the pathway and promotes growth. Indeed, high activity of the Hh pathway was identified in MCF-7 cells and overexpression of PTCH inhibited the pathway. Moreover, treatment with cyclopamine, an inhibitor of the pathway, reduced cell growth and slowed the cell cycle in these cells. Thus, unmasking of epigenetic silencing in breast cancer enabled us to discover a large number of candidate tumor suppressor genes. Further analysis suggested a role of one of these genes, PTCH, in breast cancer tumorigenesis.

Original languageEnglish (US)
Pages (from-to)139-155
Number of pages17
JournalBreast Cancer Research and Treatment
Volume105
Issue number2
DOIs
StatePublished - Oct 2007
Externally publishedYes

Keywords

  • Breast cancer
  • GLI1
  • Hedgehog pathway
  • Methylation
  • PTCH

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Unmasking of epigenetically silenced genes reveals DNA promoter methylation and reduced expression of PTCH in breast cancer'. Together they form a unique fingerprint.

Cite this