Progesterone receptor isoforms PRA and PRB differentially contribute to breast cancer cell migration through interaction with focal adhesion kinase complexes

Author:

Bellance Catherine12,Khan Junaid A.123,Meduri Geri124,Guiochon-Mantel Anne124,Lombès Marc125,Loosfelt Hugues12

Affiliation:

1. Institut National de la Santé et de la Recherche Médicale Unité 693, Le Kremlin-Bicêtre F-94276, France

2. Faculté de Médecine, Université Paris-Sud, Unité Mixte de Recherche UMR-S693, Le Kremlin-Bicêtre F-94276, France

3. Department of Physiology and Pharmacology, University of Agriculture, Faisalabad 38040, Pakistan

4. Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie, Hôpital Bicêtre, Le Kremlin-Bicêtre F-94275, France

5. Service d'Endocrinologie et Maladies de la Reproduction, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin-Bicêtre F-94275, France

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-dimethyl­amino)­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.

Publisher

American Society for Cell Biology (ASCB)

Subject

Cell Biology,Molecular Biology

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