Interactions between FGFR2 and RSK2-implications for breast cancer prognosis.

Dominika Czaplinska,Kamil Mieczkowski,Radzislaw Kordek,Rafal Sadej,Wojciech Biernat,Andrzej C Skladanowski,Anna J Zaczek,Anna Supernat,Hanna M Romanska

doi:10.1007/s13277-016-5266-9

Dominika Czaplinska, Kamil Mieczkowski + Show 7 more

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https://doi.org/10.1007/s13277-016-5266-9

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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.Electronic supplementary materialThe online version of this article (doi:10.1007/s13277-016-5266-9) contains supplementary material, which is available to authorized users.

Highlights

Fibroblast growth factor receptors (FGFRs) and their ligands (FGFs) play an important role in mammalian ontogenesis, angiogenesis and wound healing
Values of fibroblast growth factor receptor 2 (FGFR2)/ribosomal s6 kinase 2 (RSK2) correlation coefficients evaluated in the whole group of patients were increased when analysis was restricted to the TNBC subgroup only (p = 0.005 and p = 0.015 for gene and protein expression, respectively)
As a follow-on from our previous study demonstrating that FGFR2 activates RSK2 in BCa cells in vitro [19], we have undertaken an evaluation of a potential clinical significance of an interaction between FGFR2 and RSK2 in breast cancer

Summary

Introduction

Fibroblast growth factor receptors (FGFRs) and their ligands (FGFs) play an important role in mammalian ontogenesis, angiogenesis and wound healing. FGFR family consists of four tyrosine kinase receptors (FGFR1–4) that are expressed in multiple alternatively spliced variants, which define ligand specificity and downstream signalling pathways [1]. FGFR2 has been implicated in development and progression of breast cancer (BCa). Genome-wide analysis has identified single nucleotide polymorphisms (SNPs) in intron 2 of the FGFR2 gene associated with a higher risk of BCa [2]. In BCa patients, increased both nuclear and cytoplasmic FGFR2 expression correlated with lower overall and disease-free survival [3]. FGFR2 gene amplification was reported in approximately

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