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TheScientificWorldJOURNAL
Volume 9 (2009), Pages 1438-1448
http://dx.doi.org/10.1100/tsw.2009.166
Review Article

Trastuzumab Resistance: Role for Notch Signaling

1Molecular Biology Program, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA
2Department of Pathology, Oncology Institute, Cardinal Bernardin Cancer Center, Maywood, IL, USA
3Molecular and Cellular Biochemistry Program, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA

Received 3 June 2009; Revised 8 December 2009; Accepted 9 December 2009

Academic Editor: John D. Scott

Copyright © 2009 Kinnari Mehta and Clodia Osipo.

Abstract

Epidermal growth factor receptor-2 (ErbB-2/HER2) is a potent breast oncogene that has been shown to be amplified in 20% of breast cancers. Overexpression of ErbB-2 predicts for aggressive tumor behavior, resistance to some cytotoxic and antihormonal therapies, and poor overall survival. Trastuzumab, the humanized, monoclonal antibody directed against ErbB-2 has shown tremendous efficacy and improved overall survival for women when combined with a taxane-based chemotherapy. However, resistance to trastuzumab remains a major concern, most notably in women with metastatic breast cancer. Numerous mechanisms that include overexpression of alternate receptor tyrosine kinases and/or loss of critical tumor suppressors have been proposed in the last several years to elucidate trastuzumab resistance. Here we review the many possible mechanisms of action that could contribute to resistance, and novel therapies to prevent or reverse the resistant phenotype. Moreover, we provide a critical role for Notch signaling cross-talk with overlapping or new signaling networks in trastuzumab-resistant breast.