title: Progesterone receptor isoforms PRA and PRB differentially contribute to breast cancer cell migration through interaction with focal adhesion kinase complexes.
abstract: Progesterone receptor (PR) and progestins affect mammary tumorigenesis; however, the relative contributions of PR isoforms A and B (PRA and PRB, respectively) in cancer cell migration remains elusive. By using a bi-inducible MDA-MB-231 breast cancer cell line expressing PRA and/or PRB, we analyzed the effect of conditional PR isoform expression. Surprisingly, unliganded PRB but not PRA strongly enhanced cell migration as compared with PR(-) cells. 17,21-Dimethyl-19-norpregna-4,9-dien-3,20-dione (R5020) progestin limited this effect and was counteracted by the antagonist 11β-(4-dimethyl-amino)-phenyl-17β-hydroxy-17-(1-propynyl)-estra-4,9-dien-3-one (RU486). Of importance, PRA coexpression potentiated PRB-mediated migration, whereas PRA alone was ineffective. PR isoforms differentially regulated expressions of major players of cell migration, such as urokinase plasminogen activator (uPA), its inhibitor plasminogen activator inhibitor type 1, uPA receptor (uPAR), and β1-integrin, which affect focal adhesion kinase (FAK) signaling. Moreover, unliganded PRB but not PRA enhanced FAK Tyr397 phosphorylation and colocalized with activated FAK in cell protrusions. Because PRB, as well as PRA, coimmunoprecipitated with FAK, both isoforms can interact with FAK complexes, depending on their respective nucleocytoplasmic trafficking. In addition, FAK degradation was coupled to R5020-dependent turnovers of PRA and PRB. Such an effect of PRB/PRA expression on FAK signaling might thus affect adhesion/motility, underscoring the implication of PR isoforms in breast cancer invasiveness and metastatic evolution with underlying therapeutic outcomes.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale Unité 693, Le Kremlin-Bicêtre F-94276, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Bellance
authors.forename: Junaid A
authors.initials: JA
authors.lastname: Khan
authors.forename: Geri
authors.initials: G
authors.lastname: Meduri
authors.forename: Anne
authors.initials: A
authors.lastname: Guiochon-Mantel
authors.forename: Marc
authors.initials: M
authors.lastname: Lombès
authors.forename: Hugues
authors.initials: H
authors.lastname: Loosfelt
mesh_terms: D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D022001:Focal Adhesions / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D020033:Protein Isoforms; D011980:Receptors, Progesterone; D055293:Receptors, Urokinase Plasminogen Activator; C051321:SERPINE1 protein, human; C101118:progesterone receptor A; C097314:progesterone receptor B; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D014568:Urokinase-Type Plasminogen Activator