Amplitude modulation of androgen signaling by c-MYC.
Genes Dev, 2013/4/01;27(7):734-48.
Ni M[1], Chen Y, Fei T, Li D, Lim E, Liu XS, Brown M
Affiliations
PMID: 23530127DOI: 10.1101/gad.209569.112
Impact factor: 12.89
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.
MeSH terms
Androgens; Breast Neoplasms; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Genome-Wide Association Study; Hepatocyte Nuclear Factor 3-alpha; Humans; Protein Binding; Proto-Oncogene Proteins c-myc; Receptors, Androgen; Signal Transduction; Transcription Factor 7-Like 2 Protein; Transcriptional Activation
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