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

Oncogene. 2018 Apr;37(15):2008-2021. doi: 10.1038/s41388-017-0042-x. Epub 2018 Jan 25.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Hormonal / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Chromatin Assembly and Disassembly / drug effects
  • Chromatin Assembly and Disassembly / genetics
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Gene Regulatory Networks* / drug effects
  • Humans
  • MCF-7 Cells
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Microarray Analysis
  • Nuclear Receptor Coactivator 1 / physiology*
  • Transcriptional Activation / genetics
  • Transcriptome / drug effects
  • Tumor Cells, Cultured


  • Antineoplastic Agents, Hormonal
  • NCOA1 protein, human
  • Nuclear Receptor Coactivator 1