<scp>FGFR2</scp>‐<scp>RUNX2</scp> activation: An unexplored therapeutic pathway in luminal breast cancer related to tumor progression

Overcoming luminal breast cancer (BrCa) progression remains a critical challenge for improved overall patient survival. RUNX2 has emerged as a protein related to aggressiveness in triple-negative BrCa, however its role in luminal tumors remains elusive. We have previously shown that active FGFR2 (FGFR2-CA) contributes to increased tumor growth and that RUNX2 expression was high in hormone-independent mouse mammary carcinomas. To elucidate the interaction between FGFR2 and RUNX2 in human BrCa, we investigated their roles in tumor progression and treatment responsiveness. Increased FGFR2 activity resulted in higher RUNX2 expression, cell proliferation, and metastasis. In contrast, silencing FGFR2 reduced these parameters. Overexpression of RUNX2 in FGFR2-silenced cells rescued the inhibitory effects, promoting a more aggressive phenotype, even if compared with the wt RUNX2-transfected cells, which also had increased aggressiveness compared with naïve-transfected cells. RUNX2-overexpressing tumors were insensitive to endocrine- or FGFR inhibitor treatments. Notably, the CBFβ-RUNX complex inhibitor, AI-14-91, demonstrated great effectiveness in vitro. In a small cohort of luminal BrCa patients, nuclear RUNX2 expression was associated with tumor recurrence. Transcriptomic analysis strongly supported these data showing that patients with luminal carcinomas with high RUNX2 activity score have a worse progression-free interval than those with low RUNX2 activity. Our findings suggest a complex interplay between FGFR2 and RUNX2 in regulating tumor aggressiveness. This study underscores the significance of RUNX2 in luminal BrCa progression and posits RUNX2 as a promising therapeutic target and as a potential prognostic biomarker in luminal BrCa patients.