Met receptor contributes to trastuzumab resistance of Her2-overexpressing breast cancer cells

David L. Shattuck, Jamie K. Miller, Kermit L Carraway, Colleen A Sweeney

Research output: Contribution to journalArticle

274 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)1471-1477
Number of pages7
JournalCancer Research
Volume68
Issue number5
DOIs
StatePublished - Mar 1 2008

Fingerprint

Breast Neoplasms
Antibodies, Monoclonal, Humanized
Survival
Receptor Protein-Tyrosine Kinases
Therapeutics
Trastuzumab
Up-Regulation
Recurrence
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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 journalArticle

@article{41229b9713f34cc5a1a66bb127b7c385,
title = "Met receptor contributes to trastuzumab resistance of Her2-overexpressing breast cancer cells",
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.",
author = "Shattuck, {David L.} and Miller, {Jamie K.} and Carraway, {Kermit L} and Sweeney, {Colleen A}",
year = "2008",
month = "3",
day = "1",
doi = "10.1158/0008-5472.CAN-07-5962",
language = "English (US)",
volume = "68",
pages = "1471--1477",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "5",

}

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 -