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ISSN: 2157-2518

Journal of Carcinogenesis & Mutagenesis
Open Access

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Review Article

Regulation of Apoptosis by HER2 in Breast Cancer

Richard L Carpenter1 and Hui-Wen Lo1,2*

1Division of Surgical Sciences, Department of Surgery, Duke University School of Medicine, Durham, North Carolina 27710, USA

2Duke Cancer Institute, Duke University School of Medicine, Durham, North Carolina 27710, USA

*Corresponding Author:
Hui-Wen Lo
Division of Surgical Sciences
Department of Surgery (Box 3156)
Duke University School of Medicine
Duke Cancer Institute
423 MSRB I, 103 Research Drive
Durham, NC 27710, USA
E-mail: [email protected]

Received date: April 20, 2013; Accepted date: June 17, 2013; Published date: June 26, 2013

Citation: Carpenter RL, Lo HW (2013) Regulation of Apoptosis by HER2 in Breast Cancer. J Carcinogene Mutagene S7:003. doi: 10.4172/2157-2518.S7-003

Copyright: © 2013 Carpenter RL, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

HER2 is a trans-membrane receptor tyrosine kinase that activates multiple growth-promoting signaling pathways including PI3K-AKT and Ras-MAPK. Dysregulation of HER2 is a frequent occurrence in breast cancer that is associated with poor patient outcomes. A primary function of HER2 is suppressing apoptosis to enhance cell survival giving rise to uncontrolled proliferation and tumor growth. There has been much investigation into the mechanisms by which apoptosis is suppressed by HER2 in hopes of finding clinical targets for HER2-positive breast cancers as these cancers often become resistant to therapies that directly target HER2. Several apoptotic mechanisms have been shown to be deregulated in HER2-overexpressing cells with examples in both the intrinsic and extrinsic apoptotic pathways. HER2-mediated activation of PI3K-AKT signaling is required for many of the mechanisms HER2 uses to suppress apoptosis. HER2 overexpression is correlated with increases in anti-apoptotic Bcl-2 proteins including Bcl-2, Bcl-xL, and Mcl-1. HER2 also suppresses p53-mediated apoptosis by upregulation of MDM2 by activation of AKT. In addition, survivin expression is often increased with HER2 overexpression leading to inhibition of caspase activation. There is also recent evidence to suggest HER2 can directly influence apoptosis by translocation to the mitochondria to inhibit cytochrome c release. HER2 can also suppress cellular reaction to death ligands, especially TRAIL-induced apoptosis. Elucidation of the mechanisms of apoptotic suppression by HER2 suggest that clinical treatment will likely need to target multiple components of these pathways as there is redundancy in HER2-mediated cell survival. Several therapies have attempted to target Bcl-2 proteins that have promising pre-clinical results. Next-generation HER2 targeting therapies include irreversible pan-ERBB inhibitors and antibody-drug conjugates, such as T-DM1 that has very promising clinical results thus far. Further investigation should include elucidating mechanisms of resistance to HER2-targeted therapies and targeting of multiple components of HER2-mediated cell

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