PMID- 21324925
OWN - NLM
STAT- MEDLINE
DCOM- 20110421
LR  - 20230202
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 71
IP  - 5
DP  - 2011 Mar 1
TI  - Trastuzumab has preferential activity against breast cancers driven by HER2 
      homodimers.
PG  - 1871-82
LID - 10.1158/0008-5472.CAN-10-1872 [doi]
AB  - In breast cancer cells with HER2 gene amplification, HER2 receptors exist on the 
      cell surface as monomers, homodimers, and heterodimers with EGFR/HER3. The 
      therapeutic antibody trastuzumab, an approved therapy for HER2(+) breast cancer, 
      cannot block ligand-induced HER2 heterodimers, suggesting it cannot effectively 
      inhibit HER2 signaling. Hence, HER2 oligomeric states may predict the odds of a 
      clinical response to trastuzumab in HER2-driven tumors. To test this hypothesis, 
      we generated nontransformed human MCF10A mammary epithelial cells stably 
      expressing a chimeric HER2-FKBP molecule that could be conditionally induced to 
      homodimerize by adding the FKBP ligand AP1510, or instead induced to 
      heterodimerize with EGFR or HER3 by adding the heterodimer ligands EGF/TGFalpha or 
      heregulin. AP1510, EGF, and heregulin each induced growth of MCF10A cells 
      expressing HER2-FKBP. Trastuzumab inhibited homodimer-mediated but not 
      heterodimer-mediated cell growth. In contrast, the HER2 antibody pertuzumab, 
      which blocks HER2 heterodimerization, inhibited growth induced by heregulin but 
      not AP1510. Lastly, the HER2/EGFR tyrosine kinase inhibitor lapatinib blocked 
      both homodimer- and heterodimer-induced growth. AP1510 triggered phosphorylation 
      of Erk1/2 but not AKT, whereas trastuzumab inhibited AP1510-induced Erk1/2 
      phosphorylation and Shc-HER2 homodimer binding, but not TGFalpha-induced AKT 
      phosphorylation. Consistent with these observations, high levels of HER2 
      homodimers correlated with longer time to progression following trastuzumab 
      therapy in a cohort of patients with HER2-overexpressing breast cancer. Together, 
      our findings confirm the notion that HER2 oligomeric states regulate HER2 
      signaling, also arguing that trastuzumab sensitivity of homodimers may reflect 
      their inability to activate the PI3K (phosphoinositide 3-kinase)/AKT pathway. A 
      clinical implication of our results is that high levels of HER2 homodimers may 
      predict a positive response to trastuzumab.
CI  - (c)2011 AACR.
FAU - Ghosh, Ritwik
AU  - Ghosh R
AD  - Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University, 
      Nashville, Tennessee 37232, USA.
FAU - Narasanna, Archana
AU  - Narasanna A
FAU - Wang, Shizhen Emily
AU  - Wang SE
FAU - Liu, Shuying
AU  - Liu S
FAU - Chakrabarty, Anindita
AU  - Chakrabarty A
FAU - Balko, Justin M
AU  - Balko JM
FAU - Gonzalez-Angulo, Ana Maria
AU  - Gonzalez-Angulo AM
FAU - Mills, Gordon B
AU  - Mills GB
FAU - Penuel, Elicia
AU  - Penuel E
FAU - Winslow, John
AU  - Winslow J
FAU - Sperinde, Jeff
AU  - Sperinde J
FAU - Dua, Rajiv
AU  - Dua R
FAU - Pidaparthi, Sailaja
AU  - Pidaparthi S
FAU - Mukherjee, Ali
AU  - Mukherjee A
FAU - Leitzel, Kim
AU  - Leitzel K
FAU - Kostler, Wolfgang J
AU  - Kostler WJ
FAU - Lipton, Allan
AU  - Lipton A
FAU - Bates, Michael
AU  - Bates M
FAU - Arteaga, Carlos L
AU  - Arteaga CL
LA  - eng
GR  - R01 CA080195/CA/NCI NIH HHS/United States
GR  - P50 CA98131/CA/NCI NIH HHS/United States
GR  - P30 CA68485/CA/NCI NIH HHS/United States
GR  - P50 CA098258/CA/NCI NIH HHS/United States
GR  - P50 CA098131/CA/NCI NIH HHS/United States
GR  - U54 CA112970/CA/NCI NIH HHS/United States
GR  - R01 CA080195-12/CA/NCI NIH HHS/United States
GR  - P30 CA068485/CA/NCI NIH HHS/United States
GR  - CA80195/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20110215
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Quinazolines)
RN  - 0VUA21238F (Lapatinib)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - K16AIQ8CTM (pertuzumab)
RN  - P188ANX8CK (Trastuzumab)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antibodies, Monoclonal/*pharmacology
MH  - Antibodies, Monoclonal, Humanized
MH  - Antineoplastic Agents/*pharmacology
MH  - Breast Neoplasms/chemistry/drug therapy/*metabolism
MH  - Cells, Cultured
MH  - Female
MH  - Gene Expression
MH  - Gene Expression Profiling
MH  - Humans
MH  - Immunoblotting
MH  - Immunoprecipitation
MH  - Lapatinib
MH  - Middle Aged
MH  - Oligonucleotide Array Sequence Analysis
MH  - Protein Multimerization/*physiology
MH  - Quinazolines/pharmacology
MH  - Receptor, ErbB-2/chemistry/*metabolism
MH  - Signal Transduction/drug effects/physiology
MH  - Trastuzumab
PMC - PMC3221734
MID - NIHMS260803
EDAT- 2011/02/18 06:00
MHDA- 2011/04/22 06:00
PMCR- 2012/03/01
CRDT- 2011/02/18 06:00
PHST- 2011/02/18 06:00 [entrez]
PHST- 2011/02/18 06:00 [pubmed]
PHST- 2011/04/22 06:00 [medline]
PHST- 2012/03/01 00:00 [pmc-release]
AID - 0008-5472.CAN-10-1872 [pii]
AID - 10.1158/0008-5472.CAN-10-1872 [doi]
PST - ppublish
SO  - Cancer Res. 2011 Mar 1;71(5):1871-82. doi: 10.1158/0008-5472.CAN-10-1872. Epub 
      2011 Feb 15.