Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1471-1477 |
| Number of pages | 7 |
| Journal | Cancer Research |
| Volume | 68 |
| Issue number | 5 |
| DOIs | |
| State | Published - Mar 1 2008 |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
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Met receptor contributes to trastuzumab resistance of Her2-overexpressing breast cancer cells. / Shattuck, David L.; Miller, Jamie K.; Carraway, Kermit L; Sweeney, Colleen A.
In: Cancer Research, Vol. 68, No. 5, 01.03.2008, p. 1471-1477.Research output: Contribution to journal › Article
}
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.
UR - http://www.scopus.com/inward/record.url?scp=40449113978&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=40449113978&partnerID=8YFLogxK
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 -