Significance of FGFR2 – RSK2 interdependence for breast cancer progression. In vitro studies and clinical material analyses

Abstract

The members of p90 ribosomal S6 kinase (RSK) family of Ser/Thr kinases are downstream effectors of MAPK/ERK pathway that regulate diverse cellular processes including cell growth, proliferation and survival. In carcinogenesis, RSKs are thought to modulate cell motility, invasion and metastasis. Elevated level of RSK1 and RSK2 was found in about 50% of breast tumours and is associated with a poor survival outcome. The project aims to investigate the role of RSK2 kinase in breast cancer progression out at two complementary levels: in vitro studies and analyses of samples from breast cancer patients. We demonstrated that in breast epithelial and cancer cell lines stimulation of FGFR2 (fibroblast growth factor receptor 2) with FGF2 induced activation of RSK2-Tyr529 and that this new signalling pathway promoted anchorage-independent cell proliferation, formation of focal adhesions and cell migration. In clinical analyses FGFR2 showed a positive correlation with RSK2 at both protein (p = 0.003) and mRNA (p = 0.001) levels. The values of correlation coefficients were the highest in triple- -negative breast cancer (TNBC), which is more aggressive and has a poorer prognosis than other breast cancer subtypes. Moreover, expression of FGFR2 and/or activated RSK (RSK-P) significantly correlated with poor disease-free survival (DFS) of patients (p = 0.01). Taken together, our results suggest that FGFR2-RSK2 signalling pathway is associated with breast cancer progression and further studies of FGFR2-RSK2 interdependence may contribute to the development of new therapeutic strategies in the management of patients with breast cancer.