PMID- 17266042
OWN - NLM
STAT- MEDLINE
DCOM- 20070417
LR  - 20220330
IS  - 0020-7136 (Print)
IS  - 0020-7136 (Linking)
VI  - 120
IP  - 9
DP  - 2007 May 1
TI  - Downregulation of erbB3 abrogates erbB2-mediated tamoxifen resistance in breast 
      cancer cells.
PG  - 1874-82
AB  - 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 erbB2 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.
CI  - (c) 2007 Wiley-Liss, Inc.
FAU - Liu, Bolin
AU  - Liu B
AD  - Department of Pathology and College of Medicine, University of Colorado at Denver 
      and Health Sciences Center (UCDHSC), Aurora, CO, USA. Bolin.Liu@uchsc.edu
FAU - Ordonez-Ercan, Dalia
AU  - Ordonez-Ercan D
FAU - Fan, Zeying
AU  - Fan Z
FAU - Edgerton, Susan M
AU  - Edgerton SM
FAU - Yang, Xiaohe
AU  - Yang X
FAU - Thor, Ann D
AU  - Thor AD
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Int J Cancer
JT  - International journal of cancer
JID - 0042124
RN  - 0 (RNA, Small Interfering)
RN  - 094ZI81Y45 (Tamoxifen)
RN  - 42HK56048U (Tyrosine)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - EC 2.7.10.1 (Receptor, ErbB-3)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Breast Neoplasms/*drug therapy/pathology
MH  - Down-Regulation
MH  - Drug Resistance, Neoplasm
MH  - Female
MH  - Humans
MH  - Mammary Neoplasms, Experimental/*drug therapy/pathology
MH  - Mice
MH  - Phosphorylation
MH  - RNA, Small Interfering/pharmacology
MH  - Receptor, ErbB-2/*physiology
MH  - Receptor, ErbB-3/*antagonists & inhibitors/physiology
MH  - Tamoxifen/*pharmacology
MH  - Tyrosine/metabolism
EDAT- 2007/02/03 09:00
MHDA- 2007/04/18 09:00
CRDT- 2007/02/03 09:00
PHST- 2007/02/03 09:00 [pubmed]
PHST- 2007/04/18 09:00 [medline]
PHST- 2007/02/03 09:00 [entrez]
AID - 10.1002/ijc.22423 [doi]
PST - ppublish
SO  - Int J Cancer. 2007 May 1;120(9):1874-82. doi: 10.1002/ijc.22423.