title: Interactions between FGFR2 and RSK2-implications for breast cancer prognosis.
abstract: We have previously demonstrated that fibroblast growth factor receptor 2 (FGFR2) activates ribosomal s6 kinase 2 (RSK2) in mammary epithelial cells and that this pathway promotes in vitro cell growth and migration. Potential clinical significance of FGFR2 and RSK2 association has never been investigated. Herein, we have undertaken an evaluation of a possible relationship between FGFR2/RSK2 interdependence and disease outcome in breast cancer (BCa) patients. The clinical analysis was complemented by an in vitro investigation of an involvement of RSK2 in the regulation of FGFR2 function. Primary tumour samples from 152 stage I-III BCa patients were examined for FGFR2 and RSK2 gene and protein expression. FGFR2 showed a positive correlation with RSK2 at both protein (p = 0.003) and messenger RNA (mRNA) (p = 0.001) levels. Lack of both FGFR2 and activated RSK (RSK-P) significantly correlated with better disease-free survival (DFS) (p = 0.01). Patients with tumours displaying immunoreactivity for either or both FGFR2 and RSK-P had 4.89-fold higher risk of recurrence when compared to the FGFR2/RSK-P-negative subgroup. FGFR2-RSK2 interactions were verified by co-immunoprecipitation and internalization assays in HB2 mammary epithelial cell line (characterized by high endogenous FGFR2 and RSK2 expression). In vitro analyses revealed that FGFR2 and RSK2 formed an indirect complex and that activated RSK exerted a significant impact on fibroblast growth factor 2 (FGF2)-triggered internalization of FGFR2. Our results suggest that the FGFR2-RSK2 signalling pathway is involved in pathophysiology of BCa and evaluation of FGFR2/RSK-P expression may be useful in disease prognostication.
authors.affiliation: Department of Cell Biology, Intercollegiate Faculty of Biotechnology, University of Gdańsk and Medical University of Gdańsk, 80-210, Gdańsk, Poland.
authors.forename: Dominika
authors.initials: D
authors.lastname: Czaplinska
authors.affiliation: Department of Molecular Enzymology, Intercollegiate Faculty of Biotechnology, University of Gdańsk and Medical University of Gdańsk, 80-210, Gdansk, Poland.
authors.forename: Kamil
authors.initials: K
authors.lastname: Mieczkowski
authors.affiliation: Department of Cell Biology, Intercollegiate Faculty of Biotechnology, University of Gdańsk and Medical University of Gdańsk, 80-210, Gdańsk, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Supernat
authors.affiliation: Department of Molecular Enzymology, Intercollegiate Faculty of Biotechnology, University of Gdańsk and Medical University of Gdańsk, 80-210, Gdansk, Poland.
authors.forename: Andrzej C
authors.initials: AC
authors.lastname: Skladanowski
authors.affiliation: Department of Pathology, Medical University of Łódź, 92-213, Łódź, Poland.
authors.forename: Radzislaw
authors.initials: R
authors.lastname: Kordek
authors.affiliation: Department of Pathomorphology, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Biernat
authors.affiliation: Department of Cell Biology, Intercollegiate Faculty of Biotechnology, University of Gdańsk and Medical University of Gdańsk, 80-210, Gdańsk, Poland. azaczek@gumed.edu.pl.
authors.forename: Anna J
authors.initials: AJ
authors.lastname: Zaczek
authors.affiliation: Department of Pathology, Medical University of Łódź, 92-213, Łódź, Poland. hanna.romanska@gmail.com.
authors.forename: Hanna M
authors.initials: HM
authors.lastname: Romanska
authors.affiliation: Department of Molecular Enzymology, Intercollegiate Faculty of Biotechnology, University of Gdańsk and Medical University of Gdańsk, 80-210, Gdansk, Poland. rsadej@gumed.edu.pl.
authors.forename: Rafal
authors.identifier: http://orcid.org/0000-0003-2583-7299
authors.initials: R
authors.lastname: Sadej
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018275:Carcinoma, Lobular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005455:Fluorescent Antibody Technique; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; 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
keywords: Breast cancer; FGFR2; RSK2