p130Cas is an essential transducer element in ErbB2 transformation

Cabodi, S., Tinnirello, A., Bisaro, B., Tornillo, G., Camacho-Leal, M. D., Forni, G., Cojoca, R., Iezzi, M., Amici, A., Montani, M., Eva, A., Di Stefano, P., Muthuswamy, S. K., Tarone, G., Turco, E., Defilippi, P. (October 2010) p130Cas is an essential transducer element in ErbB2 transformation. Faseb J, 24 (10). pp. 3796-3808. ISSN 1530-6860 (Electronic) 0892-6638 (Linking)

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URL: https://www.ncbi.nlm.nih.gov/pubmed/20505116
DOI: 10.1096/fj.10-157347

Abstract

The ErbB2 oncogene is often overexpressed in breast tumors and associated with poor clinical outcome. p130Cas represents a nodal scaffold protein regulating cell survival, migration, and proliferation in normal and pathological cells. The functional role of p130Cas in ErbB2-dependent breast tumorigenesis was assessed by its silencing in breast cancer cells derived from mouse mammary tumors overexpressing ErbB2 (N202-1A cells), and by its reexpression in ErbB2-transformed p130Cas-null mouse embryonic fibroblasts. We demonstrate that p130Cas is necessary for ErbB2-dependent foci formation, anchorage-independent growth, and in vivo growth of orthotopic N202-1A tumors. Moreover, intranipple injection of p130Cas-stabilized siRNAs in the mammary gland of Balbc-NeuT mice decreases the growth of spontaneous tumors. In ErbB2-transformed cells, p130Cas is a crucial component of a functional molecular complex consisting of ErbB2, c-Src, and Fak. In human mammary cells, MCF10A.B2, the concomitant activation of ErbB2, and p130Cas overexpression sustain and strengthen signaling, leading to Rac1 activation and MMP9 secretion, thus providing invasive properties. Consistently, p130Cas drives N202-1A cell in vivo lung metastases colonization. These results demonstrate that p130Cas is an essential transducer in ErbB2 transformation and highlight its potential use as a novel therapeutic target in ErbB2 positive human breast cancers.-Cabodi, S., Tinnirello, A., Bisaro, B., Tornillo, G., Camacho-Leal, M. P., Forni, G., Cojoca, R., Iezzi, M., Amici, A., Montani, M., Eva, A., Di Stefano, P., Muthuswamy, S. K., Tarone, G., Turco, E., Defilippi, P. p130Cas is an essential transducer element in ErbB2 transformation.

Item Type: Paper
Uncontrolled Keywords: breast cancer, tumorigenesis, invasion, metastasis, signaling
Subjects: diseases & disorders > cancer > cancer types > breast cancer
organism description > animal > mammal > rodent > mouse
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein expression
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase > tyrosine kinase
CSHL Authors:
Communities: CSHL Cancer Center Program > Signal Transduction
CSHL labs > Muthuswamy lab
Depositing User: CSHL Librarian
Date: October 2010
Date Deposited: 28 Sep 2011 13:35
Last Modified: 28 Feb 2018 21:10
Related URLs:
URI: http://repository.cshl.edu/id/eprint/15379

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