Amplitude modulation of androgen signaling by c-MYC

Min Ni, Yiwen Chen, Teng Fei, Dan Li, Elgene Lim, X. Shirley Liu, Myles Brown

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

Androgen-stimulated growth of the molecular apocrine breast cancer subtype is mediated by an androgen receptor (AR)-regulated transcriptional program. However, the molecular details of this AR-centered regulatory network and the roles of other transcription factors that cooperate with AR in the network remain elusive. Here we report a positive feed-forward loop that enhances breast cancer growth involving AR, AR coregulators, and downstream target genes. In the absence of an androgen signal, TCF7L2 interacts with FOXA1 at AR-binding sites and represses the basal expression of AR target genes, including MYC. Direct AR regulation of MYC cooperates with AR-mediated activation of HER2/HER3 signaling. HER2/HER3 signaling increases the transcriptional activity of MYC through phosphorylation of MAD1, leading to increased levels of MYC/MAX heterodimers. MYC in turn reinforces the transcriptional activation of androgen-responsive genes. These results reveal a novel regulatory network in molecular apocrine breast cancers regulated by androgen and AR in which MYC plays a central role as both a key target and a cooperating transcription factor to drive oncogenic growth.

Original languageEnglish (US)
Pages (from-to)734-748
Number of pages15
JournalGenes and Development
Volume27
Issue number7
DOIs
StatePublished - Apr 1 2013

Keywords

  • AR
  • Breast cancer
  • Cistrome
  • FOXA1
  • MYC
  • TCF7L2

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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