Restoration of tamoxifen sensitivity in estrogen receptor-negative breast cancer cells: Tamoxifen-bound reactivated ER recruits distinctve corepressor complexes

Dipali Sharma, Neeraj K. Saxena, Nancy E. Davidson, Paula M. Vertino

Research output: Contribution to journalArticle

Abstract

Breast tumors expressing estrogen receptor-α (ER) respond well to therapeutic strategies using selective ER modulators, such as tamoxifen. However, ∼3096 of invasive breast cancers are hormone independent because they lack ER expression due to hypermethylation of ER promoter. Treatment of ER-negative breast cancer cells with demethylating agents [5-aza-2′- deoxycytidine (5-aza-dC)] and histone deacetylase (HDAC) inhibitors (trichostatin A) leads to expression of ER mRNA and functional protein. Here, we examined whether epigenetically reactivated ER is a target for tamoxifen therapy. Following treatment with trichostatin A and 5-aza-dC, the formerly unresponsive ER-negative MDA-MB-231 breast cancer cells became responsive to tamoxifen. Tamoxifen-mediated inhibition of cell growth in these cells is mediated at least in part by the tamoxifen-bound ER. Tamoxifen-bound reactivated ER induces transcriptional repression at estrogen-responsive genes by ordered recruitment of multiple distinct chromatin-modifying complexes. Using chromatin immunoprecipitation, we show recruitment of two different corepressor complexes to ER-responsive promoters in a mutually exclusive and sequential manner: the nuclear receptor corepressor-HDAC3 complex followed by nucleosome remodeling and histone deacetylation complex. The mechanistic insight provided by this study might help in designing therapeutic strategies directed toward epigenetic mechanisms in the prevention or treatment of breast cancer.

Original languageEnglish (US)
Pages (from-to)6370-6378
Number of pages9
JournalCancer Research
Volume66
Issue number12
DOIs
StatePublished - Jun 15 2006

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Restoration of tamoxifen sensitivity in estrogen receptor-negative breast cancer cells: Tamoxifen-bound reactivated ER recruits distinctve corepressor complexes'. Together they form a unique fingerprint.

  • Cite this