The miRNAome associated to CTBP1 and metabolic syndrome impacts on the outcome of Breast Cancer patients.

DUCA RB; FARRÉ PL; GRAÑA K; DALTON GN; SCALISE G; MASSILLO C; DE SIERVI A; DE LUCA P

Mar del Plata

Congreso; LXIII Reunión Annual de la Sociedad Argentina de Investigación Clínica; 2018

Sociedad Argentina de Investigación Clínica

Breast cancer (BrCa) is the leading cause of cancer death in womenand metabolic syndrome (MeS) constitutes a risk factor for thisdisease. C-terminal binding protein 1 (CTBP1) is a co-repressor oftumor suppressors activated by low NAD+/NADH ratio. Previously,we generated a MeS model by chronically feeding mice with highfat diet. We found that CTBP1 and MeS induced tumor growth andprogression regulating the expression of let-7e-3p, miR-494-3p,miR-146a-5p, miR-194-1-5p, miR-381-5p and miR-378a-3p in BrCaxenografts. The aim of this work was to investigate the role of themiRNAs modulated by CTBP1 and MeS in BrCa. We analyzed theeffect of the CTBP1/MeS-associated miRNAs in survival of BrCapatients through the bioinformatics tool PROGmiR. We found thatin almost all cases, miRNAs effects depend on ER and PR status.Thus, low expression of let-7e-3p correlated with diminished survivalin patients with BrCa ER+ and PR+, while high expression levelsare associated with a lower metastasis-free survival in patientswith BrCa ER-. Low expression of miR-494-3p is associated withdecreased metastasis-free survival in patients with BrCa PR+. Lowexpression of miR-146a-5p correlated with low metastasis-free inER+ BrCa patients. In BrCa PR- patients, miR-146a-5p and miR-194-1-5p expression is related to increased relapse-free survival, whilemiR-381-5p expression is associated with reduced metastasis-freesurvival. Interestingly, miR-378a-3p expression is associated withlow metastasis-free survival in BrCa global population. Based onthis, we selected miR-378a-3p to evaluate its effects in proliferation,adhesion and migration of BrCa cells through in vitro assays. Thus,miR-78a-3p was cloned into the expression vector pSM30. We generatedMDA-MB-231 stable-transfected cells with overexpression ofmiR-378a-3p or control cells and selected positive MDA-MB-231-derived clones by RT-qPCR. To identify microRNAome associatedwith tumor growth and progression constitutes the first step for thedevelopment of targeted therapies for BrCa associated to MeS.