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// Dominika Piasecka 1, 4 , Kamila Kitowska 1 , Dominika Czaplinska 2 , Kamil Mieczkowski 1 , Magdalena Mieszkowska 1 , Lukasz Turczyk 1 , Andrzej C. Skladanowski 1 , Anna J. Zaczek 2 , Wojciech Biernat 3 , Radzislaw Kordek 4 , Hanna M. Romanska 4 , Rafal Sadej 1 1 Department of Molecular Enzymology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Poland 2 Department of Cell Biology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Poland 3 Department of Pathomorphology, Medical University of Gdansk, Poland 4 Department of Pathology, Medical University of Lodz, Poland Correspondence to: Rafal Sadej, email: rsadej@gumed.edu.pl Hanna M. Romanska, email: hanna.romanska@gmail.com Keywords: progesterone receptor, FGFR2, breast cancer Received: April 12, 2016 Accepted: November 07, 2016 Published: November 12, 2016 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.