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Network analysis of SRC-1 reveals a novel transcription factor hub which regulates endocrine resistant breast cancer.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Browne, Alacoque L 
Charmsaz, Sara 
Fagan, Ailis 
Cosgrove, Nicola 

Abstract

Steroid receptor coactivator 1 (SRC-1) interacts with nuclear receptors and other transcription factors (TFs) to initiate transcriptional networks and regulate downstream genes which enable the cancer cell to evade therapy and metastasise. Here we took a top-down discovery approach to map out the SRC-1 transcriptional network in endocrine resistant breast cancer. First, rapid immunoprecipitation mass spectrometry of endogenous proteins (RIME) was employed to uncover new SRC-1 TF partners. Next, RNA sequencing (RNAseq) was undertaken to investigate SRC-1 TF target genes. Molecular and patient-derived xenograft studies confirmed STAT1 as a new SRC-1 TF partner, important in the regulation of a cadre of four SRC-1 transcription targets, NFIA, SMAD2, E2F7 and ASCL1. Extended network analysis identified a downstream 79 gene network, the clinical relevance of which was investigated in RNAseq studies from matched primary and local-recurrence tumours from endocrine resistant patients. We propose that SRC-1 can partner with STAT1 independently of the estrogen receptor to initiate a transcriptional cascade and control regulation of key endocrine resistant genes.

Description

Keywords

Animals, Antineoplastic Agents, Hormonal, Breast Neoplasms, Chromatin Assembly and Disassembly, Drug Resistance, Neoplasm, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Regulatory Networks, Humans, MCF-7 Cells, Mice, Mice, Inbred NOD, Mice, SCID, Microarray Analysis, Nuclear Receptor Coactivator 1, Transcriptional Activation, Transcriptome, Tumor Cells, Cultured

Journal Title

Oncogene

Conference Name

Journal ISSN

0950-9232
1476-5594

Volume Title

37

Publisher

Springer Science and Business Media LLC
Sponsorship
European Research Council (646876)
Cancer Research UK (C14303/A17197)
Cancer Research UK (20411)