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Downregulation of erbB3 abrogates erbB2‐mediated tamoxifen resistance in breast cancer cells
Author(s) -
Liu Bolin,
OrdonezErcan Dalia,
Fan Zeying,
Edgerton Susan M.,
Yang XiaoHe,
Thor Ann D.
Publication year - 2007
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.22423
Subject(s) - erbb3 , cancer research , receptor tyrosine kinase , tamoxifen , downregulation and upregulation , erbb , protein kinase b , tyrosine kinase , carcinogenesis , biology , signal transduction , chemistry , cancer , breast cancer , microbiology and biotechnology , biochemistry , genetics , gene
Receptor tyrosine kinase activity is essential for erbB2 (HER2/ neu ) promotion of breast carcinogenesis, metastasis and therapeutic resistance. erbB2 kinase can be activated by dimerization with another erbB receptor, most of which bind ligands. Of these, the erbB2/erbB3 heterodimer is the most potent oncogenic complex. erbB2 reportedly requires erbB3 to promote cellular proliferation, although this may occur without changes in erbB2 tyrosine kinase activity in some model systems. Our investigations focus on the role(s) of erbB3 in erbB2‐associated kinase activity and tamoxifen resistance. Using tumor‐derived cell lines from wild type rat c‐ neu transgenic mice and human breast cancers, we demonstrate that erbB3 plays a critical role in the activation of erbB2 tyrosine kinase activity and erbB2‐associated tumorigenesis. Mechanistically, downregulation of erbB3 by specific siRNA reduces erbB2 tyrosine phosphorylation, decreases the PI‐3K/Akt signaling, and inhibits mammary/breast cancer cell proliferation and colony formation. Specific erbB3 siRNA sensitizes erbB 2 transfected MCF‐7 cells (MCF‐7/erbB2) to tamoxifen‐associated inhibition of both cell growth and colony formation and enhances tamoxifen‐induced apoptosis, in contrast to control siRNA transfected MCF‐7/erbB2 cells which are tamoxifen‐resistant. Our data indicates that erbB2/erbB3 heterodimerization is a prerequisite for erbB2 tyrosine kinase activation in mammary/breast cancer cells and that downregulation of erbB3 inhibits erbB2‐associated procarcinogenic activity via inactivation of the PI‐3K/Akt pathway. Furthermore, erbB3 also contributes to erbB2‐mediated tamoxifen resistance and therefore may be a clinically relevant therapeutic target in addition to erbB2. © 2007 Wiley‐Liss, Inc.