FGFR1 signalling in breast cancer: dissecting expression patterns and the role of MMP-mediated nuclear localization

Fibroblast growth factor receptor (FGFRs) are critical regulators of development, homeostasis and wound healing. Dysregulated FGFR signalling is increasingly implicated in breast cancer (BCa) progression and therapy resistance. Among the FGFRs, nuclear FGFR1 is associated with poor prognosis and aggressive phenotypes. However, its cleavage and nuclear trafficking mechanisms remain poorly understood.

This PhD project used a wide range of biological, molecular and bioinformatic techniques to 1) analyze FGFR signalling in breast cancer cell lines (BCCLs) to determine how ligand specificity and proteolytic activity influence downstream outcomes 2) to investigate matrix metalloproteinase 2 (MMP2)’s role in FGFR1 cleavage, nuclear localization and downstream signalling in BCa. Bioinformatics revealed differential FGF(R) expression with FGFR1 amplification enriched in IDC (11%) and ILC (7%) subtypes analysed.This guided the selection of a panel of BCCLs (MCF-7, T47D, SKBR3 and MDA-MB-231) for use in this study. Basal protein expression demonstrated nuclear FGFR1 enrichment while receptor stimulation activated ERK, increased nuclear FGFR1, and enhanced proliferation, migration and adhesion.

Inhibition of FGFR signalling or MMP2-mediated cleavage reduced these effects, highlighting the relationship between FGFR1 signalling and proteolytic processing. Transient FGFR1b transfection confirmed full length and cleaved receptor fragments in whole cell lysates and conditioned media. Functional assays demonstrated that nuclear FGFR1 promotes aggressive cellular behaviours. Immunohistochemical examination of BCa tissue microarray (TMA) supported these findings, showing strong nuclear FGFR1 in invasive ductal carcinoma (IDC), limited MMP2 expression and nuclear FGFR2with moderate nuclear ADAM9.

These results provide novel insights into MMP2-mediated FGFR1 cleavage, nuclear trafficking and functional signalling in BCa, reinforcing nuclear FGFR1 as a potential biomarker of aggressive, therapy resistant disease. Additionally, it supports the dual targeting possibility of FGFR1 and MMP2 as a promising therapeutic avenue in BCa. These and other major findings and their implications will be discussed in this thesis