Table of Contents
Journal of Signal Transduction
Volume 2011, Article ID 804236, 8 pages
http://dx.doi.org/10.1155/2011/804236
Review Article

The Functional Crosstalk between HER2 Tyrosine Kinase and TGF-β Signaling in Breast Cancer Malignancy

Division of Tumor Cell Biology, Beckman Research Institute of City of Hope, KCRB-2007, 1500 East Duarte Road, Duarte, CA 91010, USA

Received 25 November 2010; Accepted 13 January 2011

Academic Editor: M. Gaestel

Copyright © 2011 Shizhen Emily Wang. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Accumulating evidence indicates a functional crosstalk between the HER2 (ErbB2) tyrosine kinase and the TGF-β signaling mediated by its serine/threonine kinase receptors. In HER2-overexpressing breast cancer, this crosstalk results in increased cancer cell proliferation, survival and invasion, accelerated cancer progression and metastasis in animal models, and resistance to chemotherapy and HER2-targeted therapy. The transformed cellular context with constitutively active HER2 signaling, as a consequence of HER2 gene amplification or overexpression, converts TGF-β from a tumor suppressor to a malignancy-promoting factor. TGF-β, in turn, potentiates oncogenic HER2 signaling by inducing shedding of the ErbB ligands and clustering of HER2 with integrins. In addition, TGF-β is associated with resistance to trastuzumab, an anti-HER2 therapeutic antibody. Recent mechanistic studies indicate that TGF-β and HER2 cooperate through both Smad-dependent and independent mechanisms. Blockade of HER2:TGF-β crosstalk may significantly enhance the efficiency of conventional therapies in breast cancer patients with HER2 overexpression.