HER2/neu kinase-dependent modulation of androgen receptor function through effects on DNA binding and stability

Given the role of the EGFR/HER2 family of tyrosine kinases in breast cancer, we dissected the molecular basis of Ill 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 AIR transcriptional activity. Additional genetic and pharmacologic experiments show that this modulation of AIR function is mediated by the HER2/ERBB3 pathway, not by EGFR. This HER2/ERBB3 signal stabilizes AIR protein levels and optimizes binding of AIR 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.