Met Receptor Contributes to Trastuzumab Resistance of Her2-Overexpressing Breast Cancer Cells

Her2 is overexpressed in 20% to 30% of breast tumors and correlates with reduced disease-free and overall patient survival. Trastuzumab, a humanized monoclonal antibody directed against Her2, represents the first Her2-targeted therapy, which decreases the risk of relapse and prolongs patient surviva...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2008-03, Vol.68 (5), p.1471-1477
Main Authors: SHATTUCK, David L, MILLER, Jamie K, CARRAWAY, Kermit L, SWEENEY, Colleen
Format: Article
Language:English
Subjects:
Antibodies, Monoclonal - pharmacology
Antibodies, Monoclonal, Humanized
Antineoplastic agents
Antineoplastic Agents - pharmacology
Biological and medical sciences
Breast - pathology
Breast Neoplasms - drug therapy
Breast Neoplasms - pathology
Cell Line, Tumor
Cell Proliferation
Drug Resistance, Neoplasm
Extracellular Signal-Regulated MAP Kinases - metabolism
Gene Expression Regulation, Neoplastic
Genes, erbB-2
Gynecology. Andrology. Obstetrics
Humans
Mammary gland diseases
Medical sciences
Models, Biological
Pharmacology. Drug treatments
Phosphorylation
Proto-Oncogene Proteins c-met - metabolism
Receptor, ErbB-2 - genetics
Receptor, ErbB-2 - physiology
Trastuzumab
Tumors
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Summary:Her2 is overexpressed in 20% to 30% of breast tumors and correlates with reduced disease-free and overall patient survival. Trastuzumab, a humanized monoclonal antibody directed against Her2, represents the first Her2-targeted therapy, which decreases the risk of relapse and prolongs patient survival. Resistance to trastuzumab, both inherent and treatment-acquired, represents a significant barrier to the effective treatment of Her2 (+) breast cancer. The Met receptor tyrosine kinase is aberrantly expressed in breast cancer and predicts poor patient prognosis. In this study, we find that Met is frequently expressed in Her2-overexpressing breast cancer cells, as well as Her2 (+) breast cancer. Importantly, Met contributes to trastuzumab resistance, as inhibition of Met sensitizes cells to trastuzumab-mediated growth inhibition, whereas Met activation protects cells against trastuzumab by abrogating p27 induction. Remarkably, Her2-overexpressing breast cancer cells rapidly up-regulate Met expression after trastuzumab treatment, promoting their own resistance. Our study suggests that a subset of Her2 (+) patients may benefit from combined inhibition of Her2 and Met.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-07-5962