Regulation of Runx1 in triple negative breast cancer

SOSA, SOFIA; RECOUVREUX, M. SOL; ROCHA VIEGAS, LUCIANA; ECHEVERRIA, PABLO; DANSEY, VIRGINIA; RODRIGUEZ-SEGUI, SANTIAGO; RUBINSTEIN, NATALIA

Lucca

Conferencia; Mammary Gland Gordon Conference; 2018

Recently, we have shown that RUNX1 could beinvolved in the aggressiveness of ER-/PR- breast tumor.Briefly, we reported that RUNX1 is able to promote oncogene expression (RSPO3)and to down regulate tumor suppressor gene expression (GJA1) in a Forkhead boxP3 (FOXP3)-dependent manner. Interestingly, RUNX1 has been reported tocorrelate with poor patient prognosis in human samples of TNBC. Nevertheless,RUNX1 participation in each breast cancer subtype is still under debate. Withthe aim to find new target genes regulated by RUNX1 in mammary tumor epithelialcells we studied a database of RUNX1 ChIP-seq obtained from human T lymphocyte.This database was combined and curated with expression microarrays obtainedfrom human mammary normal and breast cancer samples. This analysis reveals thatRUNX1 has the potential to positively regulate SOX4, and also to down regulatetumor suppressor genes like FST and GALTN6. At this point it is important tounderline that RUNX1 is able to up or down regulate gene expression dependingon the cofactors associated to the target promoter. Consequently, we performed ChIPassays on MDA-MB-231 and T47D cell lines that validated this predictive model. Attractively,FST has been previously described as a negative regulator of EMT in claudin-lowand metastatic tumors. Furthermore, SOX4 has been identified as a master geneable to control EMT by Ezh2 gene regulation. Remarkably, we found that Runx1gene expression and its transcriptional activity is significantly up regulatedin murine tumor cell lines treated with TGFβ (2 ng/ml) during 7 days. Evenmore, by blocking RUNX1 transcriptional activity we demonstrated that this transcriptionfactor is necessary for MDA-MB321 and LM3 cell lines migration. With the aim ofstudying how RUNX1 gene expression could be externally regulated we foundseveral potential DNA binding sites for glucocorticoid receptor (GR), amongothers. It has been shown that high GR expression on TNBC samples correlateswith a reduced overall survival and a shorter metastasis-free survival in chemotherapy-treatedpatient. Additionally, it has been described that activation of GR induces EMTand CSC renovation on TNBC cell lines. Interestingly, our data shows that RUNX1mRNA is significantly up regulated in MDA-MB-231 tumor cell lines treated withdexa (10-7M). Moreover, mifepristone-treated cells (10-7M)show a significant down regulation (around 50%) of RUNX1 gene expression.Altogether, our data suggest that RUNX1 gene expression is regulated during EMTand by GR activation and it could be considered a new molecular target in TNBC.<!-- /* Font Definitions */@font-face{font-family:"ＭＳ 明朝";panose-1:0 0 0 0 0 0 0 0 0 0;mso-font-charset:128;mso-generic-font-family:roman;mso-font-format:other;mso-font-pitch:fixed;mso-font-signature:1 134676480 16 0 131072 0;}@font-face{font-family:"ＭＳ 明朝";panose-1:0 0 0 0 0 0 0 0 0 0;mso-font-charset:128;mso-generic-font-family:roman;mso-font-format:other;mso-font-pitch:fixed;mso-font-signature:1 134676480 16 0 131072 0;}@font-face{font-family:Cambria;panose-1:2 4 5 3 5 4 6 3 2 4;mso-font-charset:0;mso-generic-font-family:auto;mso-font-pitch:variable;mso-font-signature:3 0 0 0 1 0;} /* Style Definitions */p.MsoNormal, li.MsoNormal, div.MsoNormal{mso-style-unhide:no;mso-style-qformat:yes;mso-style-parent:"";margin:0cm;margin-bottom:.0001pt;mso-pagination:widow-orphan;font-size:12.0pt;font-family:Cambria;mso-ascii-font-family:Cambria;mso-ascii-theme-font:minor-latin;mso-fareast-font-family:"ＭＳ 明朝";mso-fareast-theme-font:minor-fareast;mso-hansi-font-family:Cambria;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman";mso-bidi-theme-font:minor-bidi;mso-fareast-language:EN-US;}.MsoChpDefault{mso-style-type:export-only;mso-default-props:yes;font-family:Cambria;mso-ascii-font-family:Cambria;mso-ascii-theme-font:minor-latin;mso-fareast-font-family:"ＭＳ 明朝";mso-fareast-theme-font:minor-fareast;mso-hansi-font-family:Cambria;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman";mso-bidi-theme-font:minor-bidi;mso-fareast-language:EN-US;}@page WordSection1{size:612.0pt 792.0pt;margin:70.85pt 3.0cm 70.85pt 3.0cm;mso-header-margin:36.0pt;mso-footer-margin:36.0pt;mso-paper-source:0;}div.WordSection1{page:WordSection1;}-->