Transcriptional repression of ER through hMAPK dependent histone deacetylation by class I HDACs

Amy Plotkin, Claude Henry Volmar, Claes Wahlestedt, Nagi Ayad, Dorraya El-Ashry

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


Anti-estrogen therapies are not effective in ER− breast cancers, thus identifying mechanisms underlying lack of ER expression in ER− breast cancers is imperative. We have previously demonstrated that hyperactivation of MAPK (hMAPK) downstream of overexpressed EGFR or overexpression/amplification of Her2 represses ER protein and mRNA expression. Abrogation of hMAPK in ER− breast cancer cell lines and primary cultures causes re-expression of ER and restoration of anti-estrogen responses. This study was performed to identify mechanisms of hMAPK-induced transcriptional repression of ER. We found that ER promoter activity is significantly reduced in the presence of hMAPK signaling, yet did not identify specific promoter sequences responsible for this repression. We performed an epigenetic compound screen in an ER− breast cancer cell line that expresses hMAPK yet does not exhibit ER promoter hypermethylation. A number of HDAC inhibitors were identified and confirmed to modulate ER expression and estrogen signaling in multiple ER− cell lines and tumor samples lacking ER promoter methylation. siRNA-mediated knockdown of HDACs 1, 2, and 3 reversed the mRNA repression in multiple breast cancer cell lines and primary cultures and ER promoter-associated histone acetylation increased following MAPK inhibition. These data implicate histone deacetylation downstream of hMAPK in the observed ER mRNA repression associated with hMAPK. Importantly, histone deacetylation appears to be a common mechanism in the transcriptional repression of ER between ER− breast cancers with or without ER promoter hypermethylation.

Original languageEnglish (US)
Pages (from-to)249-263
Number of pages15
JournalBreast Cancer Research and Treatment
Issue number2
StatePublished - Sep 1 2014
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2014, Springer Science+Business Media New York.


  • Breast cancer
  • Estrogen receptor
  • HDAC
  • Histone deacetylase inhibitor
  • Hormonal status
  • MAPK
  • Transcriptional repression


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