Publication Date

2014-07-29

Availability

Open access

Embargo Period

2014-07-29

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Cancer Biology (Medicine)

Date of Defense

2014-07-23

First Committee Member

Dorraya El-Ashry

Second Committee Member

Zafar Nawaz

Third Committee Member

Nagi Ayad

Fourth Committee Member

Kerry Burnstein

Fifth Committee Member

Marc Lippman

Abstract

Estrogen receptor negative (ER-) breast cancer is more aggressive and associated with both shorter disease-free and overall survival than ER positive breast cancer. 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. In investigating the mechanisms underlying hMAPK repression of ER mRNA, 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 knock-down 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.

Keywords

breast cancer; estrogen receptor; histone deacetylase; histone acetylation; transcriptional repression

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