Luminal breast cancer (BrCa) is the most common subtype diagnosed in patients, and the major challenge is to understand the mechanisms related to the development of endocrine resistance and disease progression. RUNX2 is a transcription factor associated with tumor aggressiveness in triple-negative BrCa. Its role in luminal tumors is still unclear. Our previous studies showed that FGF2 promotes BrCa cell proliferation through FGFR2 and ligand-independent hormone receptor activation. We also observed higher RUNX2 expression in hormone-independent (HI) mouse mammary carcinomas. 
We aimed to evaluate FGFR2 and RUNX2 interaction in luminal BrCa models. IBR1, MCF7, and T47D cells were stably transfected with a constitutively active FGFR2 (R2CA), a RUNX2 expression plasmid, or an empty vector. R2CA and RUNX2 overexpression caused increased cell proliferation, HI growth in vivo, and metastasis development. Conversely, silencing FGFR2 or RUNX2 reduced these parameters. Interestingly, RUNX2 rescued the FGFR2-silenced phenotype, generating a more aggressive tumor phenotype compared to Control, shFGFR2- and RUNX2-overexpressing tumors. Additionally, RUNX2 overexpressing tumors generated an endocrine and FGFR inhibitor-resistant phenotype in vivo.
RUNX inhibitors (AI-14-91 or CADD522: CAD) reduced cell proliferation in vitro in all the cell lines. In vivo, CAD only reduced the growth of T47D tumors with endogenous RUNX2 expression (Control vs CAD treated group: 58% of tumor size-reduction; p<0.0001), suggesting the need to generate more efficacious inhibitors for in vivo use. 
In summary, our results indicate a complex interaction between FGFR2 and RUNX2 in regulating tumor progression and aggressiveness in luminal BrCa and suggest that RUNX2 expression could serve as a prognostic and predictive marker of therapy outcomes. The therapeutic effect of RUNX2 inhibitors in combination with other therapies deserves further investigation.