AR-mediated MYC induction enforces AR-driven transcription in molecular apocrine breast cancer.

  • Major finding: AR-mediated MYC induction enforces AR-driven transcription in molecular apocrine breast cancer.

  • Mechanism: AR binding triggers relief of TCF7L2 repression and cooperation between MYC and HER2 signaling.

  • Impact: This MYC-dependent feed-forward loop may drive androgen-regulated breast cancer growth.

Androgen receptor (AR)–regulated transcription is critical for the proliferation of the molecular apocrine breast cancer subtype, which is characterized by HER2 overexpression and estrogen receptor negativity. Recent studies have shown that in these tumors, AR cooperates with other transcription factors such as the pioneer factor forkhead box A1 (FOXA1) and components of the canonical WNT pathway to enhance androgen-responsive gene expression, but it is likely that other feedback loops also modulate AR signaling and restrain basal gene expression. Ni and colleagues found that transcription factor 7-like 2 (TCF7L2), a WNT effector and transcriptional repressor, interacted with FOXA1 and that its binding sites overlapped with FOXA1- and AR-binding sites in molecular apocrine breast cancer cells in the absence of androgen stimulation. TCF7L2 co-occupancy with FOXA1 at distal enhancers repressed the baseline expression of androgen-upregulated genes, including WNT pathway genes and, in particular, MYC, whereas androgen-mediated AR activation decreased TCF7L2 binding and enhanced FOXA1-facilitated AR occupancy, resulting in derepression of MYC expression. In response to AR activation, MYC binding was enriched at the promoters of AR target genes involved in translation and cell-cycle progression. Furthermore, AR-stimulated HER2/HER3 signaling cooperated with AR-induced MYC expression to amplify the AR transcriptional program; in response to androgen, HER2 promoted the phosphorylation and degradation of MAD1 via phosphoinositide 3-kinase (PI3K)/AKT signaling, enabling increased dimerization of MYC and MAX proteins at the promoters of AR target genes. Inhibition of AR or HER2 signaling diminished this interaction and impaired MYC recruitment to gene promoters, and MYC depletion reduced the expression of a subset of androgen-regulated genes. These findings identify MYC as both a target and an effector of AR signaling and delineate a positive feed-forward loop that promotes the AR-dependent growth of this breast cancer subtype.

Ni M, Chen Y, Fei T, Li D, Lim E, Liu XS, et al. Amplitude modulation of androgen signaling by c-MYC. Genes Dev 2013 Mar 25 [Epub ahead of print].