title: Amplitude modulation of androgen signaling by c-MYC.
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.
authors.affiliation: Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Ni
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Chen
authors.forename: Teng
authors.initials: T
authors.lastname: Fei
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.forename: Elgene
authors.initials: E
authors.lastname: Lim
authors.forename: X Shirley
authors.initials: XS
authors.lastname: Liu
authors.forename: Myles
authors.initials: M
authors.lastname: Brown
mesh_terms: D000728:Androgens / Q000378:metabolism*; D001943:Breast Neoplasms / Q000473:pathology; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks / Q000235:genetics / Q000502:physiology; D055106:Genome-Wide Association Study; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism; D006801:Humans; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction; D058118:Transcription Factor 7-Like 2 Protein / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D000728:Androgens; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D016271:Proto-Oncogene Proteins c-myc; D011944:Receptors, Androgen; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein