ERBB2-Mediated Transcriptional Up-regulation of the α5β1 Integrin Fibronectin Receptor Promotes Tumor Cell Survival Under Adverse Conditions

Abstract

Oncogenic activation of the receptor tyrosine kinase ERBB2 is a key event in the development of a number of epithelial malignancies. In these tumors, high levels of ERBB2 are strongly associated with metastatic disease and poor prognosis. Paradoxically, an inherent cellular response to hypermitogenic signaling by ERBB2 and other oncogenes seems to be growth arrest, rather than proliferation. Molecular characterization of this yet undefined antiproliferative state in independent cell lines overexpressing either wild-type ERBB2 or the mutationally activated receptor unveiled a dramatic induction of the A5B1 integrin fibronectin receptor. A5 Integrin up-regulation is mainly a transcriptional response mediated by the hypoxia-inducible transcription factors (HIF), leading to a massive increase in membrane-resident receptor molecules and enhanced fibronectin adhesiveness of the respective cells. Functionally, ERBB2-dependent ligation of fibronectin results in improved survival of mammary adenocarcinoma cells under adverse conditions, like serum withdrawal, hypoxia, and chemotherapy. HIF-1A is an independent predictor of poor overall survival in patients with breast cancer. In particular, HIF-1A overexpression correlates significantly with early local relapse and distant metastasis, a phenotype also highly characteristic of ERBB2-positive tumors. As HIF-1A is known to be stabilized by ERBB2 signaling under normoxic conditions, we propose that A5 integrin is a major effector in this regulatory circuit and may represent the molecular basis for the HIF-1A-dependent aggressiveness observed in ERBB2-overexpressing breast carcinomas. Hypermitogenic ERBB2 signaling and tumor hypoxia may act synergistically to favor the establishment of chemoresistant dormant micrometastatic cells frequently observed in patients with breast cancer. This new insight could be the basis for additional approaches complementing current cancer therapy. (Cancer Res 2006; 66(7): 3715-25)

ERBB2 Induces an Antiapoptotic Expression Pattern of Bcl-2 Family Members in Node-Negative Breast Cancer

“…To study the influence of ERBB2 expression on Bcl-2 family members, we used an MCF-7 cell line (MCF-7-NeuT) that allows doxycycline-induced expression of NeuT, an oncogenic version of ERBB2 (13,25). MCF-7-NeuT cells were exposed to doxycycline for 6, 12 and 24 hours as well as 3 and 14 days.…”

ERBB2 and TOP2A in Breast Cancer: A Comprehensive Analysis of Gene Amplification, RNA Levels, and Protein Expression and Their Influence on Prognosis and Prediction

“…From a biological point of view, analysis of protein function would be ideal. However, relatively large amounts of fresh frozen tissue are required for activity assays as well as protein quantification by quantitative immunoblots (34)(35)(36) which are often not available. Therefore, immunostaining is frequently employed, because paraffin material is available Fig.…”

The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis

“…Other downstream or cooperating pathways HER2 overexpression leads to increased expression of hypoxia-inducible factor 1a (HIF-1a) through Akt leading to increased expression of vascular endothelial growth factor (VEGF) and increased surface expression of fibronectin receptors (Laughner et al, 2001;Li et al, 2005;Spangenberg et al, 2006). VEGF expression is also induced by HER2 overexpression through a HIF-1a-independent mechanism (Loureiro et al, 2005).…”