Nuclear FGF2, androgen receptor and Wnt pathway activation define a targetable subset of antiprogestin-resistant luminal breast cancer.

BACKGROUND

Endocrine resistance is a major clinical challenge in luminal breast cancer. Nuclear fibroblast growth factor 2 (FGF2) and altered progesterone receptor (PR) isoform ratios have been identified as markers of antiprogestin resistance. We investigated pathways associated with FGF2 upregulation to identify new targets for antiprogestin-resistant tumours.

METHODS

PR+ T47D and T47D‑YA cell lines engineered to overexpress FGF2 were used to investigate FGF2‑driven antiprogestin resistance. Transcriptome profiling, qRT-PCR, immunohistochemistry, and in vivo assays assessed hormone receptor expression, pathway alterations, and therapeutic response. We evaluated nuclear androgen receptor (AR) and FGF2 in luminal breast cancer specimens.

RESULTS

RNA-seq showed that FGF2 overexpression dysregulated Wnt signalling, downregulated oestrogen receptor (ER) and PR, and upregulated AR expression. PR isoform B (PRB) predominated, consistent with an antiprogestin-resistant phenotype. FGF2-overexpressing xenografts showed antiprogestin resistance, increased proliferation, and lung metastasis. AR and Wnt pathway blockade impaired tumour growth, and combined treatment further reduced tumour and metastatic burden. In clinical samples, nuclear FGF2 correlated with elevated AR levels in ER+PR- and PRB-high tumours.

CONCLUSION

We identified a subset of luminal breast cancers characterised by nuclear FGF2, AR upregulation, and PR isoform imbalance. Dual AR and Wnt pathway targeting may offer a promising strategy for antiprogestin-resistant disease.