p130Cas is an essential transducer element in ErbB2 transformation.
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
Sara
S
Molecular Biotechnology Center, University of Torino, Torino, Via Nizza 52, 10126 Torino, Italy.
Tinnirello
Agata
A
Bisaro
Brigitte
B
Tornillo
Giusy
G
del Pilar Camacho-Leal
Maria
M
Forni
Guido
G
Cojoca
Rodica
R
Iezzi
Manuela
M
Amici
Augusto
A
Montani
Maura
M
Eva
Alessandra
A
Di Stefano
Paola
P
Muthuswamy
Senthil K
SK
Tarone
Guido
G
Turco
Emilia
E
Defilippi
Paola
P
D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D050719:Crk-Associated Substrate Protein / Q000235:genetics / Q000502:physiology*; D005260:Female; D020868:Gene Silencing; D018734:Genes, erbB-2; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D041681:NIH 3T3 Cells; D034741:RNA, Small Interfering; D015398:Signal Transduction
C493842:Bcar1 protein, mouse; D050719:Crk-Associated Substrate Protein; D034741:RNA, Small Interfering