Breast Cancer Research and Treatment

, Volume 105, Issue 2, pp 139–155

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
Preclinical Study

DOI: 10.1007/s10549-006-9440-4

Cite this article as:
Wolf, I., Bose, S., Desmond, J.C. et al. Breast Cancer Res Treat (2007) 105: 139. doi:10.1007/s10549-006-9440-4

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.

Keywords

Breast cancer Methylation PTCH GLI1 Hedgehog pathway 

Supplementary material

10549_2006_9440_MOESM1_ESM.xls (134 kb)
Supplemental Table 1ESM1 (XLS 135 KB)
10549_2006_9440_MOESM2_ESM.xls (168 kb)
Supplemental Table 2ESM2 (XLS 168 KB)
10549_2006_9440_MOESM3_ESM.doc (32 kb)
Supplemental Table 3ESM3 (DOC 32KB)

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Ido Wolf
    • 1
    • 5
  • Shikha Bose
    • 2
  • Julian C. Desmond
    • 1
  • Bryan T. Lin
    • 3
  • Elizabeth A. Williamson
    • 1
  • Beth Y. Karlan
    • 4
  • H. Phillip Koeffler
    • 1
  1. 1.Division of Hematology/Oncology, Cedars-Sinai Medical CenterUCLA School of MedicineLos AngelesUSA
  2. 2.Department of Anatomic Pathology, Cedars-Sinai Medical CenterUCLA School of MedicineLos AngelesUSA
  3. 3.Tarzana Regional Medical CenterTarzanaUSA
  4. 4.Women’s Cancer Research Institute, Cedars-Sinai Medical CenterUCLA School of MedicineLos AngelesUSA
  5. 5.Institute of OncologyChaim-Sheba Medical CenterTel-HashomerIsrael

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