TY - JOUR
T1 - Transcriptional repression of ER through hMAPK dependent histone deacetylation by class I HDACs
AU - Plotkin, Amy
AU - Volmar, Claude Henry
AU - Wahlestedt, Claes
AU - Ayad, Nagi
AU - El-Ashry, Dorraya
N1 - Publisher Copyright:
© 2014, Springer Science+Business Media New York.
PY - 2014/9/1
Y1 - 2014/9/1
N2 - 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.
AB - 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.
KW - Breast cancer
KW - Estrogen receptor
KW - HDAC
KW - Histone deacetylase inhibitor
KW - Hormonal status
KW - MAPK
KW - Transcriptional repression
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UR - http://www.scopus.com/inward/citedby.url?scp=84929989448&partnerID=8YFLogxK
U2 - 10.1007/s10549-014-3093-5
DO - 10.1007/s10549-014-3093-5
M3 - Article
C2 - 25129342
AN - SCOPUS:84929989448
SN - 0167-6806
VL - 147
SP - 249
EP - 263
JO - Breast Cancer Research and Treatment
JF - Breast Cancer Research and Treatment
IS - 2
ER -