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

被引：272

作者：

Mellinghoff, IK

Vivanco, I

Kwon, A

Tran, C

Wongvipat, J

Sawyers, CL ^{[1
]}

机构：

[1] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA

[2] Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA

[3] Univ Calif Los Angeles, David Geffen Sch Med, Dept Urol, Los Angeles, CA 90095 USA

[4] Univ Calif Los Angeles, David Geffen Sch Med, Inst Mol Biol, Los Angeles, CA 90095 USA

[5] Univ Calif Los Angeles, David Geffen Sch Med, Howard Hughes Med Inst, Los Angeles, CA 90095 USA

来源：

CANCER CELL | 2004年 / 6卷 / 05期

关键词：

D O I：

10.1016/j.ccr.2004.09.031

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：517 / 527

页数：11

共 73 条

[1]

Agus DB, 1999, CANCER RES, V59, P4761

[2] Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth [J].