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

  • Br J Cancer. 2026 Jun;134(11):1671-1682. doi: 10.1038/s41416-026-03420-2.
Virginia Figueroa  1 ,  Marcela I Coianis  1 ,  Ana Sahores  1 ,  Gabriela Pataccini  1 ,  Martín C Abba  2 ,  Andrés Elía  1 ,  María May  1 ,  Silvia I Vanzulli  1 ,  Paula Martínez Vázquez  3 ,  Javier Burruchaga  3 ,  Florencia Torres  3 ,  Carol A Sartorius  4 ,  Claudia Lanari  1 ,  Caroline A Lamb  5
Affiliations
  • 1. Laboratorio de Carcinogénesis Hormonal, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Ciudad de Buenos Aires, Argentina.
  • 2. Centro de Investigaciones Inmunológicas Básicas y Aplicadas (CINIBA), Facultad de Ciencias Médicas, Universidad Nacional de la Plata, La Plata, Argentina.
  • 3. Hospital de Agudos Magdalena V de Martínez, General Pacheco, Buenos Aires, Argentina.
  • 4. Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • 5. Laboratorio de Carcinogénesis Hormonal, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Ciudad de Buenos Aires, Argentina. [email protected].
PMID: 41935240 DOI: 10.1038/s41416-026-03420-2
Abstract

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.

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