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ERBB2-mediated transcriptional up-regulation of the alpha5beta1 integrin fibronectin receptor promotes tumor cell survival under adverse conditions.
- Source :
-
Cancer research [Cancer Res] 2006 Apr 01; Vol. 66 (7), pp. 3715-25. - Publication Year :
- 2006
-
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 alpha5beta1 integrin fibronectin receptor. alpha5 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-1alpha is an independent predictor of poor overall survival in patients with breast cancer. In particular, HIF-1alpha overexpression correlates significantly with early local relapse and distant metastasis, a phenotype also highly characteristic of ERBB2-positive tumors. As HIF-1alpha is known to be stabilized by ERBB2 signaling under normoxic conditions, we propose that alpha5 integrin is a major effector in this regulatory circuit and may represent the molecular basis for the HIF-1alpha-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.
- Subjects :
- Breast Neoplasms genetics
Breast Neoplasms metabolism
Cell Line, Tumor
Cell Survival physiology
Gene Expression Regulation, Neoplastic
Humans
Integrin alpha5 biosynthesis
Integrin alpha5 genetics
Integrin alpha5beta1 genetics
Integrin beta1 biosynthesis
Integrin beta1 genetics
RNA, Messenger biosynthesis
RNA, Messenger genetics
Receptor, ErbB-2 biosynthesis
Receptor, ErbB-2 genetics
Signal Transduction
Transfection
Up-Regulation
Breast Neoplasms pathology
Integrin alpha5beta1 biosynthesis
Receptor, ErbB-2 physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0008-5472
- Volume :
- 66
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 16585198
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-05-2823