TY - JOUR
T1 - Met receptor contributes to trastuzumab resistance of Her2-overexpressing breast cancer cells
AU - Shattuck, David L.
AU - Miller, Jamie K.
AU - Carraway, Kermit L
AU - Sweeney, Colleen A
PY - 2008/3/1
Y1 - 2008/3/1
N2 - 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, promotingtheir own resistance. Our study suggests that a subset of Her2 (+) patients may benefit from combined inhibition of Her2 and Met.
AB - 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, promotingtheir own resistance. Our study suggests that a subset of Her2 (+) patients may benefit from combined inhibition of Her2 and Met.
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U2 - 10.1158/0008-5472.CAN-07-5962
DO - 10.1158/0008-5472.CAN-07-5962
M3 - Article
C2 - 18316611
AN - SCOPUS:40449113978
VL - 68
SP - 1471
EP - 1477
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0099-7013
IS - 5
ER -