Neddylation cooperates with multiple phosphorylation to enhance FGFR1 stability and drive breast cancer progression.

BACKGROUND

Fibroblast growth factor receptor 1 (FGFR1) is frequently overexpressed in breast cancer (BC), yet the mechanisms governing its protein stabilization remain unclear. This study investigates the role of neddylation, a ubiquitin-like modification, in sustaining FGFR1 levels and driving malignant progression in BC.

METHODS

The interaction between FGFR1 and the neddylation pathway was explored using clinical databases and experimental models. After characterizing FGFR1 neddylation via immunofluorescence and co-immunoprecipitation, we examined protein stability and signaling pathways following pharmacological (MLN4924) or genetic (NAE1 knockdown) neddylation inhibition. The therapeutic relevance was tested in BC cell lines and xenograft models, with its prognostic significance determined via bioinformatic tools.

RESULTS

Elevated FGFR1 significantly correlated with lymph node metastasis and reduced survival in patients. Core neddylation components, NAE1 and NEDD8, were upregulated in multiple breast cancer cell lines and essential for sustaining FGFR1 protein stability. Inhibiting neddylation induced FGFR1 degradation via the ubiquitin-proteasome system without altering mRNA levels. We identified a synergistic relationship between neddylation and FGFR1 phosphorylation that coordinately enhanced FGFR1 stabilization, activated downstream mTOR signaling, and suppressed Bax. Functionally, MLN4924 inhibited BC cell proliferation and migration, effects rescued by recombinant human FGF2 (rhFGF2) addition. In vivo, MLN4924 effectively suppressed tumor growth and reduced FGFR1/p-mTOR levels, mimicking the efficacy of the FGFR inhibitor Erdafitinib. Clinically, co-expression of FGFR1, NAE1, and NEDD8 predicted poor patient outcomes.

CONCLUSION

These findings implicate the neddylation-FGFR1 axis as a critical oncogenic pathway in BC. Targeting this pathway represents a promising therapeutic strategy for patients with aberrant FGFR1 expression.