title: p130Cas over-expression impairs mammary branching morphogenesis in response to estrogen and EGF.
abstract: p130Cas adaptor protein regulates basic processes such as cell cycle control, survival and migration. p130Cas over-expression has been related to mammary gland transformation, however the in vivo consequences of p130Cas over-expression during mammary gland morphogenesis are not known. In ex vivo mammary explants from MMTV-p130Cas transgenic mice, we show that p130Cas impairs the functional interplay between Epidermal Growth Factor Receptor (EGFR) and Estrogen Receptor (ER) during mammary gland development. Indeed, we demonstrate that p130Cas over-expression upon the concomitant stimulation with EGF and estrogen (E2) severely impairs mammary morphogenesis giving rise to enlarged multicellular spherical structures with altered architecture and absence of the central lumen. These filled acinar structures are characterized by increased cell survival and proliferation and by a strong activation of Erk1/2 MAPKs and Akt. Interestingly, antagonizing the ER activity is sufficient to re-establish branching morphogenesis and normal Erk1/2 MAPK activity. Overall, these results indicate that high levels of p130Cas expression profoundly affect mammary morphogenesis by altering epithelial architecture, survival and unbalancing Erk1/2 MAPKs activation in response to growth factors and hormones. These results suggest that alteration of morphogenetic pathways due to p130Cas over-expression might prime mammary epithelium to tumorigenesis.
authors.affiliation: Molecular Biotechnology Center (MBC), Department of Genetics, Biology and Biochemistry, University of Turin, Turin, Italy.
authors.forename: Maria del Pilar
authors.initials: Mdel P
authors.lastname: Camacho Leal
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pincini
authors.forename: Giusy
authors.initials: G
authors.lastname: Tornillo
authors.forename: Elisa
authors.initials: E
authors.lastname: Fiorito
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bisaro
authors.forename: Elisa
authors.initials: E
authors.lastname: Di Luca
authors.forename: Emilia
authors.initials: E
authors.lastname: Turco
authors.forename: Paola
authors.initials: P
authors.lastname: Defilippi
authors.forename: Sara
authors.initials: S
authors.lastname: Cabodi
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D050719:Crk-Associated Substrate Protein / Q000235:genetics / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation; D008321:Mammary Glands, Animal / Q000254:growth & development / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009024:Morphogenesis / Q000235:genetics; D009924:Organ Culture Techniques; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D050719:Crk-Associated Substrate Protein; D004967:Estrogens; D011960:Receptors, Estrogen; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020929:Mitogen-Activated Protein Kinase Kinases