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 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.
Mellinghoff
Ingo K
IK
Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
Vivanco
Igor
I
Kwon
Andrew
A
Tran
Chris
C
Wongvipat
John
J
Sawyers
Charles L
CL
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004273:DNA, Neoplasm / Q000378:metabolism; D066246:ErbB Receptors / Q000502:physiology; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines; D011758:Pyrroles; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D011944:Receptors, Androgen; C410026:PKI 166; C494918:AKT1 protein, human