title: TGF-β autocrine pathway and MAPK signaling promote cell invasiveness             and in vivo mammary adenocarcinoma tumor progression.
abstract: Breast cancer progression and metastasis have been linked to abnormal signaling             by transforming growth factor-β (TGF-β) cytokines. In early-stage breast cancers,             TGF-β exhibits tumor suppressor activity by repressing cell proliferation and             inducing cell death, whereas in advanced-stage tumors, TGF-β promotes invasion             and metastatic dissemination. The molecular mechanisms underlying pro-oncogenic             activities of TGF-β are not fully understood. The present study validates the             role of TGF-β signaling in cancer progression and explores mediators of pro-oncogenic             TGF-β activities using the LM3 mammary adenocarcinoma cell line, derived from             a spontaneous murine mammary adenocarcinoma. Expression of kinase-inactive TGF-β             receptors decreased both basal and TGF-β-induced invasion. Analysis of signal             transduction mediators showed that p38MAPK and MEK contribute to TGF-β stimulation             of cell motility and invasion. TGF-β disrupted the epithelial actin structures             supporting cell-cell adhesions, and increased linear actin filaments. Moreover,             MEK and p38MAPK pathways showed opposite effects on actin remodeling in response             to TGF-β. Blockade of Raf-MEK signaling enhanced TGF-β induction of actin stress-fibers             whereas p38MAPK inhibitors blocked this effect. A novel observation was made that             TGF-β rapidly activates the actin nucleation Arp2/3 complex. In addition, TGF-β             stimulated matrix metalloproteinase MMP-9 secretion via a MAPK-independent pathway.             Experiments using syngeneic mice showed that kinase-inactive TGF-β receptors inhibit             the first stages of LM3 tumor growth in vivo. Our studies demonstrate that autocrine             TGF-β signaling contributes to the invasive behavior of mammary carcinoma cells.             Moreover, we show that both MAPK-dependent and -independent pathways are necessary             for TGF-β-induced effects. Therefore, MEK-ERK and p38 MAPK pathways are potential             venues for therapeutic intervention in pro-oncogenic TGF-β signaling.
authors.affiliation: Department of Oncology, Montefiore Medical Center, Bronx, NY                     10467, USA.
authors.forename: María Cecilia
authors.initials: MC
authors.lastname: Daroqui
authors.forename: Paula
authors.initials: P
authors.lastname: Vazquez
authors.forename: Elisa
authors.initials: E
authors.lastname: Bal de Kier Joffé
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Bakin
authors.forename: Lydia I
authors.initials: LI
authors.lastname: Puricelli
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D018450:Disease Progression; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D009361:Neoplasm Invasiveness; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases