RUNX2 expression correlates with tumor progression in luminal breast cancer patients
Yamil D. Mahmoud1, Silvia Vanzulli1, María Sol Rodriguez1, Eunice Spengler2, Paula Martínez Vazquez2, Javier Burruchaga2, Caroline A Lamb1, Isabel A Lüthy1, Claudia Lanari1, Cecilia Pérez Piñero1,
1.Instituto de Biología y Medicina Experimental (IBYME), CONICET, Buenos Aires, Argentina 2.Hospital Zonal de Agudos “Magdalena V de Martínez”, General Pacheco, Argentina
Luminal breast cancer (BrCa) is the most common subtype diagnosed, with major challenges in understanding the development of endocrine resistance and subsequent disease progression. RUNX2, a transcription factor (TF) linked to aggressiveness in triple-negative BrCa, has an unclear role in luminal BrCa. Our previous studies showed a correlation between FGFR2 and RUNX2 in ER+ breast cancer patients. Our aim was to determine if RUNX2 expression is associated with BrCa progression and its potential use as a prognostic marker in luminal BrCa. An exploratory study was done using BrCa samples from the Hospital Zonal de Agudos ‘Magdalena V. de Martínez.’ RUNX2 expression was assessed by immunohistochemistry (IHC) in primary tumor samples from non-progressors (n=26) and progressors (n=18). Progressors had higher RUNX2+ tumor cells and intensity scores in nuclei and cytoplasm. RUNX2 was also observed in cancer-associated fibroblasts, with higher staining scores in progressors, though not statistically significant. Then, we analyzed RUNX2 mRNA expression and its inferred activity in TCGA-BrCa patients categorized by PAM50. RUNX2 activity was among the 25 most variable TF, differing from gene expression, and was higher in Luminal A and Normal-like subtypes. ESR1 activity positively correlated with RUNX2 gene expression, while the gene expression correlated negatively. High RUNX2 activity was associated with worse progression-free interval (PFI), while high mRNA levels were linked to worse overall survival. High RUNX2 activity scores correlated with lower PFI in Luminal B patients. Notably, 89% of Luminal A patients had high RUNX2 activity scores, compared to only 11% of Luminal B patients. Our findings align with IHC studies, highlighting RUNX2’s significant role in BrCa progression and suggesting that RUNX2 expression could serve as a prognostic and a predictive marker of therapy outcomes.