Amplitude modulation of androgen signaling by c-MYC

Genes Dev. 2013 Apr 1;27(7):734-48. doi: 10.1101/gad.209569.112. Epub 2013 Mar 25.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Androgens / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic
  • Gene Regulatory Networks / genetics
  • Gene Regulatory Networks / physiology
  • Genome-Wide Association Study
  • Hepatocyte Nuclear Factor 3-alpha / metabolism
  • Humans
  • Protein Binding
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Receptors, Androgen / metabolism
  • Signal Transduction*
  • Transcription Factor 7-Like 2 Protein / metabolism
  • Transcriptional Activation

Substances

  • Androgens
  • FOXA1 protein, human
  • Hepatocyte Nuclear Factor 3-alpha
  • Proto-Oncogene Proteins c-myc
  • Receptors, Androgen
  • TCF7L2 protein, human
  • Transcription Factor 7-Like 2 Protein