title: Met receptor acts uniquely for survival and morphogenesis of EGFR-dependent normal mammary epithelial and cancer cells.
abstract: Mammary gland development and breast cancer growth require multiple factors both of endocrine and paracrine origin. We analyzed the roles of Epidermal Growth Factor Receptor (EGFR) and Hepatocyte Growth Factor Receptor (Met) in mammary epithelial cells and mammary tumor cells derived from a mutated-ErbB2 transgenic mice. By using highly specific tyrosine kinase inhibitors we found that MCF-10A and NMuMG mammary epithelial cell lines are totally dependent on EGFR activation for their growth and survival. Proliferation and 3D-morphogenesis assays showed that HGF had no role in maintaining mammary cell viability, but was the only cytokine able to rescue EGFR-inhibited mammary cells. Insulin-Like Growth Factor-I (IGF-I), basic-Fibroblast Growth Factor (b-FGF) and Neuregulin, which are well known mammary morphogenic factors, did not rescue proliferation or morphogenesis in these cell lines, following EGFR inhibition. Similarly, ErbB2-driven tumor cells are EGFR-dependent and also display HGF-mediated rescue. Western-blot analysis of the signaling pathways involved in rescue after EGFR inhibition indicated that concomitant ERK1/2 and AKT activation was exclusively driven by Met, but not by IGF-I or b-FGF. These results describe a unique role for EGFR and Met in mammary epithelial cells by showing that similar pathways can be used by tumorigenic cells to sustain growth and resist to EGFR-directed anti-tumorigenic drugs.
authors.affiliation: Department of Veterinary Science, University of Torino, Grugliasco (TO), Italy. paolo.accornero@unito.it
authors.forename: Paolo
authors.initials: P
authors.lastname: Accornero
authors.forename: Silvia
authors.initials: S
authors.lastname: Miretti
authors.forename: Francesca
authors.initials: F
authors.lastname: Bersani
authors.forename: Elena
authors.initials: E
authors.lastname: Quaglino
authors.forename: Eugenio
authors.initials: E
authors.lastname: Martignani
authors.forename: Mario
authors.initials: M
authors.lastname: Baratta
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development* / Q000473:pathology; D042361:Mammary Glands, Human / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D017228:Hepatocyte Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D019859:Proto-Oncogene Proteins c-met; D018719:Erb-b2 Receptor Tyrosine Kinases; C524056:Erbb2 protein, mouse