HER2/neu kinase-dependent modulation of androgen receptor function through effects on DNA binding and stability - PubMed (original) (raw)
HER2/neu kinase-dependent modulation of androgen receptor function through effects on DNA binding and stability
Ingo K Mellinghoff et al. Cancer Cell. 2004 Nov.
Free article
Abstract
Given the role of the EGFR/HER2 family of tyrosine kinases in breast cancer, we dissected the molecular basis of EGFR/HER2 kinase signaling in prostate cancer. Using the small molecule dual EGFR/HER2 inhibitor PKI-166, we show that the biologic effects of EGFR/HER-2 pathway inhibition are caused by reduced AR transcriptional activity. Additional genetic and pharmacologic experiments show that this modulation of AR function is mediated by the HER2/ERBB3 pathway, not by EGFR. This HER2/ERBB3 signal stabilizes AR protein levels and optimizes binding of AR to promoter/enhancer regions of androgen-regulated genes. Surprisingly, the downstream signaling pathway responsible for these effects appears to involve kinases other than Akt. These data suggest that the HER2/ERBB3 pathway is a critical target in hormone-refractory prostate cancer.
Comment in
- HER2/HER3 heterodimers in prostate cancer: Whither HER1/EGFR?
Freeman MR. Freeman MR. Cancer Cell. 2004 Nov;6(5):427-8. doi: 10.1016/j.ccr.2004.10.018. Cancer Cell. 2004. PMID: 15542423
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