PMID- 19671734
OWN - NLM
STAT- MEDLINE
DCOM- 20100119
LR  - 20200930
IS  - 1538-8514 (Electronic)
IS  - 1535-7163 (Linking)
VI  - 8
IP  - 8
DP  - 2009 Aug
TI  - An oncogenic isoform of HER2 associated with locally disseminated breast cancer 
      and trastuzumab resistance.
PG  - 2152-62
LID - 10.1158/1535-7163.MCT-09-0295 [doi]
AB  - The HER2-targeted therapy trastuzumab is widely used for the treatment of 
      patients with metastatic breast tumors overexpressing HER2. However, an objective 
      response is observed in only 12% to 24% of patients treated with trastuzumab as a 
      single agent and initial responders regress in <6 months (1-3). The reason for 
      the clinical failure of trastuzumab in this setting remains unclear. Here we show 
      that local lymph node-positive disease progression in 89% of breast cancer 
      patients with HER2-positive tumors involves the HER2 oncogenic variant 
      HER2Delta16. We further show that ectopic expression of HER2Delta16, but not 
      wild-type HER2, promotes receptor dimerization, cell invasion, and trastuzumab 
      resistance of NIH3T3 and MCF-7 tumor cell lines. The potentiated metastatic and 
      oncogenic properties of HER2Delta16 were mediated through direct coupling of 
      HER2Delta16 to Src kinase. Cotargeting of HER2Delta16 and Src kinase with the 
      single-agent tyrosine kinase inhibitor dasatinib resulted in Src inactivation, 
      destabilization of HER2Delta16, and suppressed tumorigenicity. Activated Src 
      kinase was also observed in 44% of HER2Delta16-expressing breast carcinomas 
      underscoring the potential clinical implications of coupled HER2Delta16 and Src 
      signaling. Our results suggest that HER2Delta16 expression is an important 
      genetic event driving trastuzumab-refractory breast cancer. We propose that 
      successful targeted therapeutics for intervention of aggressive HER2-positive 
      breast cancers will require a strategy to suppress HER2Delta16 oncogenic 
      signaling. One possibility involves a therapeutic strategy employing single-agent 
      tyrosine kinase inhibitors to disengage the functionally coupled oncogenic 
      HER2Delta16 and Src tyrosine kinase pathways.
FAU - Mitra, Doyel
AU  - Mitra D
AD  - 1Department of Pathology, University of Colorado-Denver, Aurora, Colorado, USA.
FAU - Brumlik, Michael J
AU  - Brumlik MJ
FAU - Okamgba, Stella U
AU  - Okamgba SU
FAU - Zhu, Yun
AU  - Zhu Y
FAU - Duplessis, Tamika T
AU  - Duplessis TT
FAU - Parvani, Jenny G
AU  - Parvani JG
FAU - Lesko, Samuel M
AU  - Lesko SM
FAU - Brogi, Edi
AU  - Brogi E
FAU - Jones, Frank E
AU  - Jones FE
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090811
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Protein Isoforms)
RN  - EC 2.7.10.1 (ERBB2 protein, human)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - P188ANX8CK (Trastuzumab)
SB  - IM
MH  - Animals
MH  - Antibodies, Monoclonal/*pharmacology/therapeutic use
MH  - Antibodies, Monoclonal, Humanized
MH  - Antineoplastic Agents/*pharmacology/therapeutic use
MH  - Breast Neoplasms/*drug therapy/enzymology/genetics
MH  - Cell Line, Tumor
MH  - Drug Resistance, Neoplasm
MH  - Female
MH  - Fluorescent Antibody Technique
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Mice
MH  - NIH 3T3 Cells
MH  - Protein Isoforms/genetics/metabolism
MH  - Receptor, ErbB-2/*genetics/*metabolism
MH  - Signal Transduction
MH  - Transfection
MH  - Trastuzumab
EDAT- 2009/08/13 09:00
MHDA- 2010/01/20 06:00
CRDT- 2009/08/13 09:00
PHST- 2009/08/13 09:00 [entrez]
PHST- 2009/08/13 09:00 [pubmed]
PHST- 2010/01/20 06:00 [medline]
AID - 1535-7163.MCT-09-0295 [pii]
AID - 10.1158/1535-7163.MCT-09-0295 [doi]
PST - ppublish
SO  - Mol Cancer Ther. 2009 Aug;8(8):2152-62. doi: 10.1158/1535-7163.MCT-09-0295. Epub 
      2009 Aug 11.