title: Identification of a GαGβγ, AKT and PKCα signalome associated with invasive             growth in two genetic models of human breast cancer cell epithelial-to-mesenchymal             transition.
abstract: The epithelial-to-mesenchymal transition (EMT) confers an aggressive subtype             associated with chemotherapy resistance in epithelial cancers. However, the mechanisms             underlying the EMT and its associated signaling dysfunctions are still poorly             understood. In two genetic models of MCF-7 breast cancer cells induced to EMT             by WISP-2 silencing and Snail transformation, we investigated the status of several             signaling elements downstream of G-protein receptors (GPR) and their functional             roles in the invasive growth potential. We report that the E-cadherin repressors             Slug, Zeb1/2 and Twist are overexpressed in these EMT cells characterized by a             triple negative phenotype (loss of estrogen ERα and progesterone PRA/PRB receptors,             no HER2 amplification), combined with loss of the alternative GPR30 estrogen receptor             and induction of the invasive growth in collagen type I gels. Ectopic Snail expression             suppressed WISP-2 transcripts and down-regulated WISP-2 gene promoter expression             in transfected cells. Accordingly, WISP-2 transcripts and Wisp-2 protein were             depleted in these two convergent models of BC cell EMT. The EMT caused dominance             of several proinvasive pathways downstream of GPR, including GαGβγ subunits, PKCα,             AKT and c-Jun induction, constitutive activation of the actin-remodeling GTPase             Rac1, coupled with growth responses (more cells at S and G2/M phases of the cell             cycle), in line with inhibition of the p27kip1/cyclin-dependent kinase CDK3 cascade.             RNA interference or selective inhibitors targeting GαGβγ subunits (BIM-46187,             gallein), PKCα (Gö6976, MT477, sh-RNAs) and PI3K-AKT (wortmannin) alleviated the             invasive phenotype. In contrast, MCF-7 cells in EMT showed signaling independence             to inhibitors of HER family tyrosine kinases and the mitogen- and stress-activated             protein kinases. Our study suggests that the signaling protagonists GαGβγ, PKCα             and PI3K-AKT are promising candidates as predictive molecular biomarkers and therapeutic             targets in the management of clinical BC in EMT.
authors.affiliation: Laboratory of Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine and Université Pierre et Marie Curie, Paris 6, Paris, France.
authors.forename: Radia
authors.initials: R
authors.lastname: Ouelaa-Benslama
authors.forename: Olivier
authors.initials: O
authors.lastname: De Wever
authors.forename: An
authors.initials: A
authors.lastname: Hendrix
authors.forename: Michèle
authors.initials: M
authors.lastname: Sabbah
authors.forename: Kathleen
authors.initials: K
authors.lastname: Lambein
authors.forename: David
authors.initials: D
authors.lastname: Land
authors.forename: Grégoire
authors.initials: G
authors.lastname: Prévost
authors.forename: Marc
authors.initials: M
authors.lastname: Bracke
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.forename: Annette K
authors.initials: AK
authors.lastname: Larsen
authors.forename: Shahin
authors.initials: S
authors.lastname: Emami
authors.forename: Christian
authors.initials: C
authors.lastname: Gespach
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms; D055511:CCN Intercellular Signaling Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D003510:Cyclohexanes / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D020962:Heterotrimeric GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D037342:Pertussis Toxin / Q000494:pharmacology; D010641:Phenotype; D011379:Prognosis; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014966:Xanthenes / Q000494:pharmacology
chemical_list: C533004:7-(2-amino-1-oxo-3-thio-propyl)-8-cyclohexylmethyl-2-phenyl-5,6,7,8-tetrahydro-imidazo-(1,2a)-pyrazine dimer, hydrochloride; D014408:Biomarkers, Tumor; D055511:CCN Intercellular Signaling Proteins; C413323:CCN5 protein, human; D003510:Cyclohexanes; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D012097:Repressor Proteins; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D014966:Xanthenes; C007820:gallein; D037342:Pertussis Toxin; D051057:Proto-Oncogene Proteins c-akt; D051571:Protein Kinase C-alpha; D020928:Mitogen-Activated Protein Kinases; D020962:Heterotrimeric GTP-Binding Proteins