TY - JOUR
T1 - Global gene repression by the steroid receptor coactivator SRC-1 promotes oncogenesis
AU - Walsh, Claire A.
AU - Bolger, Jarlath C.
AU - Byrne, Christopher
AU - Cocchiglia, Sinead
AU - Hao, Yuan
AU - Fagan, Ailis
AU - Qin, Li
AU - Cahalin, Aoife
AU - McCartan, Damian
AU - McIlroy, Marie
AU - O'Gaora, Peadar
AU - Xu, Jianming
AU - Hill, Arnold D.
AU - Young, Leonie S.
PY - 2014/1/5
Y1 - 2014/1/5
N2 - Transcriptional control is the major determinant of cell fate. The steroid receptor coactivator (SRC)-1 enhances the activity of the estrogen receptor in breast cancer cells, where it confers cell survival benefits. Here, we report that a global analysis of SRC-1 target genes suggested that SRC-1 also mediates transcriptional repression in breast cancer cells. Combined SRC-1 and HOXC11 ChIPseq analysis identified the differentiation marker, CD24, and the apoptotic protein, PAWR, as direct SRC-1/HOXC11 suppression targets. Reduced expression of both CD24 and PAWR was associated with disease progression in patients with breast cancer, and their expression was suppressed in metastatic tissues. Investigations in endocrine-resistant breast cancer cell lines and SRC-1 -/-/PyMT mice confirmed a role for SRC-1 and HOXC11 in downregulation of CD24 and PAWR. Through bioinformatic analysis and liquid chromatography/mass spectrometry, we identified AP1 proteins and Jumonji domain containing 2C (JMD2C/KDM4C), respectively, as members of the SRC-1 interactome responsible for transcriptional repression. Our findings deepen the understanding of how SRC-1 controls transcription in breast cancers.
AB - Transcriptional control is the major determinant of cell fate. The steroid receptor coactivator (SRC)-1 enhances the activity of the estrogen receptor in breast cancer cells, where it confers cell survival benefits. Here, we report that a global analysis of SRC-1 target genes suggested that SRC-1 also mediates transcriptional repression in breast cancer cells. Combined SRC-1 and HOXC11 ChIPseq analysis identified the differentiation marker, CD24, and the apoptotic protein, PAWR, as direct SRC-1/HOXC11 suppression targets. Reduced expression of both CD24 and PAWR was associated with disease progression in patients with breast cancer, and their expression was suppressed in metastatic tissues. Investigations in endocrine-resistant breast cancer cell lines and SRC-1 -/-/PyMT mice confirmed a role for SRC-1 and HOXC11 in downregulation of CD24 and PAWR. Through bioinformatic analysis and liquid chromatography/mass spectrometry, we identified AP1 proteins and Jumonji domain containing 2C (JMD2C/KDM4C), respectively, as members of the SRC-1 interactome responsible for transcriptional repression. Our findings deepen the understanding of how SRC-1 controls transcription in breast cancers.
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U2 - 10.1158/0008-5472.CAN-13-2133
DO - 10.1158/0008-5472.CAN-13-2133
M3 - Article
C2 - 24648347
AN - SCOPUS:84900021697
SN - 0008-5472
VL - 74
SP - 2533
EP - 2544
JO - Cancer Research
JF - Cancer Research
IS - 9
ER -