PMID- 29367763 OWN - NLM STAT- MEDLINE DCOM- 20190312 LR - 20240210 IS - 1476-5594 (Electronic) IS - 0950-9232 (Print) IS - 0950-9232 (Linking) VI - 37 IP - 15 DP - 2018 Apr TI - Network analysis of SRC-1 reveals a novel transcription factor hub which regulates endocrine resistant breast cancer. PG - 2008-2021 LID - 10.1038/s41388-017-0042-x [doi] AB - 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. FAU - Browne, Alacoque L AU - Browne AL AD - Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons, Dublin, Ireland. FAU - Charmsaz, Sara AU - Charmsaz S AD - Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons, Dublin, Ireland. FAU - Vareslija, Damir AU - Vareslija D AUID- ORCID: 0000-0003-1000-0357 AD - Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons, Dublin, Ireland. FAU - Fagan, Ailis AU - Fagan A AD - Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons, Dublin, Ireland. FAU - Cosgrove, Nicola AU - Cosgrove N AD - Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons, Dublin, Ireland. FAU - Cocchiglia, Sinead AU - Cocchiglia S AD - Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons, Dublin, Ireland. FAU - Purcell, Siobhan AU - Purcell S AD - Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons, Dublin, Ireland. FAU - Ward, Elspeth AU - Ward E AD - Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons, Dublin, Ireland. FAU - Bane, Fiona AU - Bane F AD - Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons, Dublin, Ireland. FAU - Hudson, Lance AU - Hudson L AD - Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons, Dublin, Ireland. FAU - Hill, Arnold D AU - Hill AD AD - Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons, Dublin, Ireland. FAU - Carroll, Jason S AU - Carroll JS AD - Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, UK. FAU - Redmond, Aisling M AU - Redmond AM AD - Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, UK. FAU - Young, Leonie S AU - Young LS AD - Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons, Dublin, Ireland. lyoung@rcsi.ie. LA - eng GR - 20411/CRUK_/Cancer Research UK/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180125 PL - England TA - Oncogene JT - Oncogene JID - 8711562 RN - 0 (Antineoplastic Agents, Hormonal) RN - EC 2.3.1.48 (NCOA1 protein, human) RN - EC 2.3.1.48 (Nuclear Receptor Coactivator 1) SB - IM MH - Animals MH - Antineoplastic Agents, Hormonal/*therapeutic use MH - Breast Neoplasms/*drug therapy/*genetics/pathology MH - Chromatin Assembly and Disassembly/drug effects/genetics MH - Drug Resistance, Neoplasm/*genetics MH - Female MH - Gene Expression Profiling MH - Gene Expression Regulation, Neoplastic MH - *Gene Regulatory Networks/drug effects MH - Humans MH - MCF-7 Cells MH - Mice MH - Mice, Inbred NOD MH - Mice, SCID MH - Microarray Analysis MH - Nuclear Receptor Coactivator 1/*physiology MH - Transcriptional Activation/genetics MH - Transcriptome/drug effects MH - Tumor Cells, Cultured PMC - PMC5895607 COIS- The authors declare that they have no competing interests. EDAT- 2018/01/26 06:00 MHDA- 2019/03/13 06:00 PMCR- 2018/01/25 CRDT- 2018/01/26 06:00 PHST- 2017/03/23 00:00 [received] PHST- 2017/09/29 00:00 [accepted] PHST- 2017/09/26 00:00 [revised] PHST- 2018/01/26 06:00 [pubmed] PHST- 2019/03/13 06:00 [medline] PHST- 2018/01/26 06:00 [entrez] PHST- 2018/01/25 00:00 [pmc-release] AID - 10.1038/s41388-017-0042-x [pii] AID - 42 [pii] AID - 10.1038/s41388-017-0042-x [doi] PST - ppublish SO - Oncogene. 2018 Apr;37(15):2008-2021. doi: 10.1038/s41388-017-0042-x. Epub 2018 Jan 25.