title: KISS1R signaling promotes invadopodia formation in human breast cancer cell via β-arrestin2/ERK.
abstract: Kisspeptins (KPs), peptide products of the KISS1 gene are endogenous ligands for the kisspeptin receptor (KISS1R), a G protein-coupled receptor. In numerous cancers, KISS1R signaling plays anti-metastatic roles. However, we have previously shown that in breast cancer cells lacking the estrogen receptor (ERα), kisspeptin-10 stimulates cell migration and invasion by cross-talking with the epidermal growth factor receptor (EGFR), via a β-arrestin-2-dependent mechanism. To further define the mechanisms by which KISS1R stimulates invasion, we determined the effect of down-regulating KISS1R expression in triple negative breast cancer cells. We found that depletion of KISS1R reduced their mesenchymal phenotype and invasiveness. We show for the first time that KISS1R signaling induces invadopodia formation and activation of key invadopodia proteins, cortactin, cofilin and membrane type I matrix metalloproteases (MT1-MMP). Moreover, KISS1R stimulated invadopodia formation occurs via a new pathway involving a β-arrestin2 and ERK1/2-dependent mechanism, independent of Src. Taken together, our findings suggest that targeting the KISS1R signaling axis might be a promising strategy to inhibit invasiveness and metastasis.
authors.affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Cameron G
authors.initials: CG
authors.lastname: Goertzen
authors.affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Dragan
authors.affiliation: Department of Oncology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada; Department of Biochemistry, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada; Department of Surgery, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada; London Regional Cancer Program, London, Ontario, Canada.
authors.forename: Eva
authors.initials: E
authors.lastname: Turley
authors.affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada; Department of Obstetrics and Gynecology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada; Lawson Health Research Institute, London, Ontario, Canada; The Children's Health Research Institute, London, Ontario, Canada.
authors.forename: Andy V
authors.initials: AV
authors.lastname: Babwah
authors.affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada; Department of Oncology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada; Lawson Health Research Institute, London, Ontario, Canada. Electronic address: moshmi.bhattacharya@schulich.uwo.ca.
authors.forename: Moshmi
authors.initials: M
authors.lastname: Bhattacharya
mesh_terms: D019390:Arrestins / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D051338:Cofilin 1 / Q000378:metabolism; D051356:Cortactin / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D000069261:Podosomes / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000074502:Receptors, Kisspeptin-1; D015398:Signal Transduction / Q000187:drug effects; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605254:ARRB2 protein, human; D019390:Arrestins; D002070:Butadienes; D051338:Cofilin 1; D051356:Cortactin; C118688:KISS1R protein, human; D009570:Nitriles; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; C113580:U 0126; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D053511:Matrix Metalloproteinase 14
keywords: Invadopodia; Invasion; KISS1R; Kisspeptin; Triple negative breast cancer; β-Arrestin