Participation of Runx1 in triple negative breast cancer

PABLO C. ECHEVERRIA; NATALIA RUBINSTEIN.; LUCIANA ROCHA VIEGAS; SANTIAGO RODRIGUEZ SEGUI; SOFIA MARIA SOSA; VIRGINIA DANSEY; MARIA SOL RECOUVREUX

Conferencia; Mammary Gland Gordon Conference; 2018

Recently, we have shown that RUNX1 could be involved in the aggressiveness of ER-/PR-breast tumor. Briefly, we reported that RUNX1 is able to promote oncogene expression (RSPO3) and to downregulate tumor suppressor gene expression (GJA1) in a Forkhead box P3 (FOXP3)-dependent manner. Interestingly, RUNX1 has been reported to correlate with poor patient prognosis in human samples of TNBC. However, RUNX1 participation in each breast cancer subtypes is still under debate. With the aim to find new target genes regulated by RUNX1 in mammary tumor epithelial cells we studieda database of RUNX1 ChIP-seq obtained from human T lymphocyte. This database was combined and curatedwith expression microarrays obtained from human mammary normal and TNBC samples. This analysis revealsthat RUNX1 has the potential to positively regulate SOX4, and also to down regulate tumorsuppressor genes like FST and GALTN6. At this point it isimportant to underline that RUNX1 is able to up or down regulate gene expression depending on the cofactorsassociated to the target promoter. Subsequently, we performed ChIP assays on MDA-MB-231 cell line that validated this predictive model. Attractively, FST has been previously described as a negative regulator of EMT in claudin-low and metastatic tumors. Furthermore, SOX4 has been identified as a master gene able tocontrol EMT by Ezh2 gene regulation. Remarkably, we found that Runx1 geneexpression and transcriptional activity is significantly up regulated in Py2T murine tumor cell line treated with TGFβ during 7 days. Even more, by blocking RUNX1 transcriptional activity we demonstrated that this protein is necessary for TNBC cell line migration.With the aim of studying how RUNX1 gene expression could be externally regulated we found several potentialDNA binding sites for glucocorticoid receptor (GR), among others. It has been shown that high GR expressionon TNBC samples correlates with a reduced overall survival and a shorter metastasis-free survival inchemotherapy-treated patient. Additionally, it has been described that activation of GR induces EMT and CSC renovation on TNBC cell lines. Interestingly, our data shows that RUNX1 mRNA is significantly up regulated in MDA-MB-231 tumor cell lines treated with dexa (10-7M). Moreover, mifepristone-treated cells (10-7M) show a significant down regulation (around50%) of RUNX1 gene expression. Altogether, our data suggest that RUNX1 gene expression is regulated during EMT and by GR activation and it could be considered a new molecular target in TNBC.