Abstract
HER2 receptor dimerization is a critical step in the HER2 activation process. Here, we demonstrated that heat shock protein gp96 on cell membrane interacts with HER2, facilitates HER2 dimerization and promotes cell proliferation. Cell membrane gp96 levels were observed to correlate with HER2 phosphorylation in primary breast tumors. Finally, we provide evidence that targeting gp96 with a specific monoclonal antibody led to decreased cell growth and increased apoptosis in vitro, and suppression of tumor growth in vivo. Our work represents a new therapeutic strategy for inhibiting HER2 signaling in cancer.
Keywords:
HER2 dimerization; breast cancer; cell membrane gp96; grp94; targeted therapy.
© 2014 UICC.
MeSH terms
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Animals
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Antibodies, Monoclonal / administration & dosage
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Antibodies, Monoclonal / pharmacology
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / pharmacology
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Breast Neoplasms / drug therapy
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Cell Line, Transformed
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Cell Line, Tumor
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Cell Membrane / metabolism
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Cell Proliferation
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Disease Models, Animal
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Female
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Gene Expression
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Heterografts
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Humans
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Isografts
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Membrane Glycoproteins / antagonists & inhibitors
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism*
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Mice
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Mice, Transgenic
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Phosphorylation
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Protein Multimerization*
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Receptor, ErbB-2 / antagonists & inhibitors
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Receptor, ErbB-2 / chemistry
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Receptor, ErbB-2 / genetics
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Receptor, ErbB-2 / metabolism*
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Signal Transduction
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Tumor Burden
Substances
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Antibodies, Monoclonal
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Antineoplastic Agents
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Membrane Glycoproteins
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endoplasmin
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Receptor, ErbB-2