p130Cas promotes invasiveness of three-dimensional ErbB2-transformed mammary acinar structures by enhanced activation of mTOR/p70S6K and Rac1.
ErbB2 over-expression is detected in approximately 25% of invasive breast cancers and is strongly associated with poor patient survival. We have previously demonstrated that p130Cas adaptor is a crucial mediator of ErbB2 transformation. Here, we analysed the molecular mechanisms through which p130Cas controls ErbB2-dependent invasion in three-dimensional cultures of mammary epithelial cells. Concomitant p130Cas over-expression and ErbB2 activation enhance PI3K/Akt and Erk1/2 MAPK signalling pathways and promote invasion of mammary acini. By using pharmacological inhibitors, we demonstrate that both signalling cascades are required for the invasive behaviour of p130Cas over-expressing and ErbB2 activated acini. Erk1/2 MAPK and PI3K/Akt signalling triggers invasion through distinct downstream effectors involving mTOR/p70S6K and Rac1 activation, respectively. Moreover, in silico analyses indicate that p130Cas expression in ErbB2 positive human breast cancers significantly correlates with higher risk to develop distant metastasis, thus underlying the value of the p130Cas/ErbB2 synergism in regulating breast cancer invasion. In conclusion, high levels of p130Cas favour progression of ErbB2-transformed cells towards an invasive phenotype.
Tornillo
Giusy
G
Molecular Biology Center, Department of Genetics, Biology and Biochemistry, University of Torino, Via Nizza 52, Torino, Italy.
Bisaro
Brigitte
B
Camacho-Leal
Maria del Pilar
Mdel P
Galiè
Mirco
M
Provero
Paolo
P
Di Stefano
Paola
P
Turco
Emilia
E
Defilippi
Paola
P
Cabodi
Sara
S
D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D050719:Crk-Associated Substrate Protein / Q000096:biosynthesis / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D021621:Imaging, Three-Dimensional; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D051058:Oncogene Protein v-akt / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D050719:Crk-Associated Substrate Protein; D020928:Mitogen-Activated Protein Kinases; D051058:Oncogene Protein v-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D020830:rac1 GTP-Binding Protein; C493841:BCAR1 protein, human; C107953:RAC1 protein, human; C546842:MTOR protein, human