RUNX2 overexpression generates endocrine resistance in human luminal breast cancer xenografts

T47D and IBH6 cells that overexpress RUNX2 show high levels of FGFR2 and FGF2, supporting the hypothesis that FGF2 increases RUNX2 and, in turn, RUNX2 increases FGF2, maintaining a positive loop. However, in these models RUNX2 overexpression generates tumors resistant to FGFR inhibitor therapy and show a more aggressive phenotype compared with control tumors.T47D and IBH6 are luminal breast cancer cells that express ER and PR. Our goal is to explore the role of RUNX2 and its relationship with hormone receptors in BrCa. The aim of this work was to evaluate the effect of endocrine therapy in RUNX2 overexpressing tumors.RUNX2 and control cells (C, empty vector) were injected into the flank of NSG mice. Animals were treated for 3 weeks with an antiestrogen (Fulvestrant FUL, 0.5mg/week) or an antiprogestin (MFP, 6mg pellets). Control tumors showed a significant growth inhibition with the therapy (C-T47D p<0.0001 C vs FUL and MFP; C-IBH6 p<0.0001 C vs FUL), a lower Ki67 index (C-T47D: p<0.0001 C vs FUL, p<0.05 C vs MFP, C-IBH6 p<0.05 C vs FUL) and higher stromal remodeling compared with untreated ones. In both models, RUNX2 tumors were resistant to endocrine therapy and all animals bearing RUNX2-T47D tumors developed lung metastasis. Our conclusion is that RUNX2 promotes BrCa progression and is a key player in the acquisition of endocrine resistance. We emphasize the development of RUNX2 inhibitors to use in combination with standard therapy for BrCa treatment. Fil: Rodríguez, Maria Sol. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Riggio, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina