PhD project: FGFR1 Signalling in Breast Cancer: Dissecting Expression Patterns and the Role of MMP-Mediated Nuclear Localization

Fibroblast growth factor receptors (FGFRs) regulate development, homeostasis, and wound healing, but their dysregulation contributes to breast cancer (BCa) progression and therapy resistance. Nuclear FGFR1, in particular, is linked to poor prognosis and aggressive phenotypes, though its cleavage and nuclear trafficking remain unclear.

This PhD project (Ms Giselle Laquis) investigated how ligand specificity, molecular subtype, and proteolytic activity shape FGFR signalling in breast cancer cell lines, focusing on the role of matrix metalloproteinase 2 (MMP2) in FGFR1 cleavage and nuclear localization. Bioinformatic analyses identified FGFR1 amplification in luminal subtypes, guiding cell line selection (MCF-7, T47D, SKBR3, MDA-MB-231). Experimental data showed that receptor activation increased nuclear FGFR1 and enhanced proliferation, migration, and adhesion, whereas inhibition of FGFR or MMP2 reduced these effects.

Tissue microarray analysis confirmed strong nuclear FGFR1 and moderate MMP2 expression in invasive ductal carcinoma, supporting a mechanistic link between the two. Overall, the study reveals MMP2-mediated FGFR1 cleavage and nuclear trafficking as key drivers of aggressive BCa and highlights dual targeting of FGFR1 and MMP2 as a potential therapeutic strategy

This research looks at a group of proteins called fibroblast growth factor receptors (FGFRs), which help control how cells grow, repair, and stay healthy. When these receptors stop working properly, they can make breast cancer grow faster and become harder to treat. One of them, FGFR1, is often found inside the cell nucleus in aggressive breast cancers, but it wasn’t clear how it gets there or what causes it to move.

In this study, we explored how FGFR1 is cut by another protein called MMP2, allowing part of it to move into the nucleus. Once inside, FGFR1 helps cancer cells grow, move, and spread more easily. Blocking either FGFR1 or MMP2 reduced these harmful effects.

We also examined breast cancer tissue samples and found that high levels of nuclear FGFR1 and MMP2 were common in more aggressive tumours. These findings suggest that targeting both FGFR1 and MMP2 together could be a new way to treat difficult forms of breast cancer.

1. FGFR1 amplification is enriched in luminal breast cancer subtypes, as revealed by bioinformatic analyses.

2. Basal expression studies showed nuclear localisation of FGFR1 in multiple breast cancer cell lines (MCF-7, T47D, SKBR3, MDA-MB-231).

3. Ligand stimulation (FGFs) activated ERK signalling, increased nuclear FGFR1 levels, and enhanced cell proliferation, migration, and adhesion.

4. Inhibition of FGFR signalling or MMP2 activity significantly reduced these oncogenic effects.

5. MMP2 mediates FGFR1 cleavage, producing full-length and cleaved receptor fragments detected in cell lysates and conditioned media.

6. Transient FGFR1b transfection confirmed generation of both full-length and cleaved forms, supporting proteolytic processing.

7. Nuclear FGFR1 promotes aggressive cellular behaviours in functional assays.

8. Tissue microarray (TMA) analysis of breast cancer specimens demonstrated:

(a) Strong nuclear FGFR1 expression in invasive ductal carcinoma (IDC).

(b) Moderate MMP2 expression.

(c) Limited nuclear FGFR2 and ADAM9.

These findings identify a functional FGFR1–MMP2 axis that drives aggressive and therapy-resistant breast cancer phenotypes.

The data support nuclear FGFR1 as a biomarker of poor prognosis and propose dual targeting of FGFR1 and MMP2 as a potential therapeutic strategy.