title: Role of the protein kinase BRAF in the pathogenesis of endometriosis.
abstract: Mitogen-activated protein kinases (MAPKs) are involved in the proliferation and survival of endometriotic lesions. Vemurafenib (PLX4032) is a novel protein kinase inhibitor that targets BRAF, a member of the MAPK pathway. The present study tested the in vitro and in vivo effects of PLX4032 on endometriotic cells.
  
  
  
  We conducted a laboratory study in a tertiary-care university hospital from January 2013 to September 2013. We enrolled a cohort of 40 patients: 20 with histologically proven endometriosis and 20 unaffected women. A thorough surgical examination of the abdominopelvic cavity was performed on all of the study participants. Ex vivo stromal and epithelial cells were extracted from endometrial and endometriotic biopsies from both sets of patients. Proliferation, apoptosis, pERK/ERK ratio, cell cycle regulation (Cyclin D1 and CDK4) and inflammation (PTGS2) were explored with and without PLX4032 treatment. Human endometriotic lesions were implanted into 40 nude mice that were separated into two groups according to PLX4032 or vehicle treatment, which they received for four weeks, before sacrifice and histological examination.
  
  
  
  Treating endometriotic cells with PLX4032 abrogated the phosphorylation of ERK, significantly reducing the pERK/ERK ratio in both epithelial and stromal cells from endometriotic women compared to the controls (p < 0.05). In addition, treatment with PLX4032 significantly decreased proliferation in both stromal and epithelial cells with a concomitant decrease in Cyclin D1/CDK4 complex and PTGS2 levels. Using a murine model of endometriosis, we observed that PLX4032-treated mice displayed a significant decrease in implant volume compared to the initial size; a slight, but non-significant, increase in size was observed in the vehicle-treated mice.
  
  
  
  Our data suggest that MAPKs and BRAF are involved in the pathogenesis of endometriosis. PLX4032-induced inhibition of BRAF controlled endometriotic growth, both in vitro and in vivo, and could constitute a promising target for the treatment of endometriosis.
authors.affiliation: a Sorbonne Paris Cité, Faculté de Médecine, Assistance Publique - Hôpitaux de Paris (AP-HP), Groupe Hospitalier Universitaire (GHU) Ouest, Centre Hospitalier Universitaire (CHU) Cochin, Department of Gynecology Obstetrics II and Reproductive Medicine , Université Paris Descartes , Paris , France.|b Department of Development, Reproduction and Cancer, Institut Cochin, INSERM U1016, Equipe Pr Batteux , Université Paris Descartes, Sorbonne Paris Cité , Paris , France.
authors.forename: Pietro
authors.initials: P
authors.lastname: Santulli
authors.affiliation: a Sorbonne Paris Cité, Faculté de Médecine, Assistance Publique - Hôpitaux de Paris (AP-HP), Groupe Hospitalier Universitaire (GHU) Ouest, Centre Hospitalier Universitaire (CHU) Cochin, Department of Gynecology Obstetrics II and Reproductive Medicine , Université Paris Descartes , Paris , France.|b Department of Development, Reproduction and Cancer, Institut Cochin, INSERM U1016, Equipe Pr Batteux , Université Paris Descartes, Sorbonne Paris Cité , Paris , France.
authors.forename: Louis
authors.initials: L
authors.lastname: Marcellin
authors.affiliation: b Department of Development, Reproduction and Cancer, Institut Cochin, INSERM U1016, Equipe Pr Batteux , Université Paris Descartes, Sorbonne Paris Cité , Paris , France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Chouzenoux
authors.affiliation: b Department of Development, Reproduction and Cancer, Institut Cochin, INSERM U1016, Equipe Pr Batteux , Université Paris Descartes, Sorbonne Paris Cité , Paris , France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Boulard
authors.affiliation: c Department of Pathology , Hôpital Cochin, AP-HP , Paris , France.
authors.forename: Pierre-Alexandre
authors.initials: PA
authors.lastname: Just
authors.affiliation: b Department of Development, Reproduction and Cancer, Institut Cochin, INSERM U1016, Equipe Pr Batteux , Université Paris Descartes, Sorbonne Paris Cité , Paris , France.
authors.forename: Carole
authors.initials: C
authors.lastname: Nicco
authors.affiliation: b Department of Development, Reproduction and Cancer, Institut Cochin, INSERM U1016, Equipe Pr Batteux , Université Paris Descartes, Sorbonne Paris Cité , Paris , France.
authors.forename: Christiane
authors.initials: C
authors.lastname: Chereau
authors.affiliation: d Obstetrics and Gynecology, Department of Molecular and Developmental Medicine , University of Siena , Siena , Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Tosti
authors.affiliation: a Sorbonne Paris Cité, Faculté de Médecine, Assistance Publique - Hôpitaux de Paris (AP-HP), Groupe Hospitalier Universitaire (GHU) Ouest, Centre Hospitalier Universitaire (CHU) Cochin, Department of Gynecology Obstetrics II and Reproductive Medicine , Université Paris Descartes , Paris , France.|b Department of Development, Reproduction and Cancer, Institut Cochin, INSERM U1016, Equipe Pr Batteux , Université Paris Descartes, Sorbonne Paris Cité , Paris , France.
authors.forename: Charles
authors.initials: C
authors.lastname: Chapron
authors.affiliation: b Department of Development, Reproduction and Cancer, Institut Cochin, INSERM U1016, Equipe Pr Batteux , Université Paris Descartes, Sorbonne Paris Cité , Paris , France.|e Department of Immunology , Hôpital Cochin, AP-HP , Paris , France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Batteux
mesh_terms: D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004715:Endometriosis / Q000188:drug therapy* / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D000077484:Vemurafenib; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases
keywords: BRAF; MAPK; PLX4032; Vemurafenib; endometriosis