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

Amplitude modulation of androgen signaling by c-MYC.

Author information

1
Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.

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.

PMID:
23530127
PMCID:
PMC3639415
DOI:
10.1101/gad.209569.112
[Indexed for MEDLINE]
Free PMC Article

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