title: Fibroblast growth factor signalling induces loss of progesterone receptor in breast cancer cells.
abstract: We have recently demonstrated that, fibroblast growth factor 2 (FGFR2), signalling via ribosomal S6 kinase 2 (RSK2), promotes progression of breast cancer (BCa). Loss of progesterone receptor (PR), whose activity in BCa cells can be stimulated by growth factor receptors (GFRs), is associated with poor patient outcome. Here we showed that FGF7/FGFR2 triggered phosphorylation of PR at Ser294, PR ubiquitination and subsequent receptor`s degradation via the 26S proteasome pathway in BCa cells. We further demonstrated that RSK2 mediated FGF7/FGFR2-induced PR downregulation. In addition, a strong synergistic effect of FGF7 and progesterone (Pg), reflected in the enhanced anchorage-independent growth and cell migration, was observed. Analysis of clinical material demonstrated that expression of PR inversely correlated with activated RSK (RSK-P) (p = 0.016). Patients with RSK-P(+)/PR(-) tumours had 3.629-fold higher risk of recurrence (p = 0.002), when compared with the rest of the cohort. Moreover, RSK-P(+)/PR(-) phenotype was shown as an independent prognostic factor (p = 0.006). These results indicate that the FGF7/FGFR2-RSK2 axis promotes PR turnover and activity, which may sensitize BCa cells to stromal stimuli and contribute to the progression toward steroid hormone negative BCa.
authors.affiliation: Department of Molecular Enzymology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Poland.|Department of Pathology, Medical University of Lodz, Poland.
authors.forename: Dominika
authors.initials: D
authors.lastname: Piasecka
authors.affiliation: Department of Molecular Enzymology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Poland.
authors.forename: Kamila
authors.initials: K
authors.lastname: Kitowska
authors.affiliation: Department of Cell Biology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Poland.
authors.forename: Dominika
authors.initials: D
authors.lastname: Czaplinska
authors.affiliation: Department of Molecular Enzymology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Poland.
authors.forename: Kamil
authors.initials: K
authors.lastname: Mieczkowski
authors.affiliation: Department of Molecular Enzymology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Mieszkowska
authors.affiliation: Department of Molecular Enzymology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Poland.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Turczyk
authors.affiliation: Department of Molecular Enzymology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Poland.
authors.forename: Andrzej C
authors.initials: AC
authors.lastname: Skladanowski
authors.affiliation: Department of Cell Biology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Poland.
authors.forename: Anna J
authors.initials: AJ
authors.lastname: Zaczek
authors.affiliation: Department of Pathomorphology, Medical University of Gdansk, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Biernat
authors.affiliation: Department of Pathology, Medical University of Lodz, Poland.
authors.forename: Radzislaw
authors.initials: R
authors.lastname: Kordek
authors.affiliation: Department of Pathology, Medical University of Lodz, Poland.
authors.forename: Hanna M
authors.initials: HM
authors.lastname: Romanska
authors.affiliation: Department of Molecular Enzymology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Poland.
authors.forename: Rafal
authors.initials: R
authors.lastname: Sadej
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality; D045744:Cell Line, Tumor; D005260:Female; D051523:Fibroblast Growth Factor 7 / Q000502:physiology*; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000502:physiology*; D011980:Receptors, Progesterone / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C496453:FGF7 protein, human; D011980:Receptors, Progesterone; D051523:Fibroblast Growth Factor 7; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease
keywords: FGFR2; breast cancer; progesterone receptor