Global gene repression by the steroid receptor coactivator SRC-1 promotes oncogenesis.

Abstract

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.

• Authors: Claire A Walsh, Jarlath C Bolger, Christopher Byrne, Sinead Cocchiglia, Yuan Hao, Ailis Fagan, Li Qin, Aoife Cahalin, Damian McCartan, Marie McIlroy, Peadar O'Gaora, Jianming Xu, Arnold D Hill, Leonie S Young
• Journal: Cancer research (Cancer Res) Vol. 74 Issue 9 Pg. 2533-44 (May 01 2014) ISSN: 1538-7445 [Electronic] United States
• PMID: 24648347 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 AACR.

Chemical References

• Apoptosis Regulatory Proteins
• CD24 Antigen
• CD24 protein, human
• HOXC11 protein, human
• Homeodomain Proteins
• KDM4C protein, human
• prostate apoptosis response-4 protein
• Jumonji Domain-Containing Histone Demethylases
• Nuclear Receptor Coactivator 1

Topics

• Animals
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Binding Sites
• Breast Neoplasms (genetics, metabolism, mortality)
• CD24 Antigen (genetics, metabolism)
• Carcinogenesis (genetics, metabolism)
• Disease-Free Survival
• Down-Regulation
• Female
• Gene Expression Regulation, Neoplastic
• Gene Silencing
• Homeodomain Proteins (physiology)
• Humans
• Jumonji Domain-Containing Histone Demethylases (metabolism)
• Kaplan-Meier Estimate
• MCF-7 Cells
• Mice
• Mice, Knockout
• Nuclear Receptor Coactivator 1 (physiology)
• Promoter Regions, Genetic