CtBP1 protein and metabolic syndrome impact on miRNAs expression profile associated to breast cancer

DE SIERVI, A; DALTON, GN; FARRÉ, PL; MASSILLO, C; PORRETTI, J; DUCA, RB; DE LUCA, P; SCALISE, GD; GRAÑA, KD

Ciudad Autónoma de Buenos AIres

Congreso; Reunión Conjunta de Sociedades de Biociencias 2017; 2017

Sociedad Argentina de Investigación Clínica

Breast cancer (BrCa) is the main cause of cancer death in women and metabolic syndrome (MeS) increases the incidence and aggressiveness of this disease. C-terminal Binding Protein (CtBP1) is a corepressor of tumor suppressors activated by the low NAD+/NADH ratio. Previously, we generated a murine MeS model by chronically feeding animals with high fat diet. We found that CtBP1 and MeS induced BrCa growth and progression. Using microarray technology we showed that CtBP1 hyperactivation by MeS regulated the expression of multiple miRNAs in BrCa xenografts. Bioinformatic analysis using miRSystem resource allowed us to identify one cluster of miRNAs involved in cell proliferation (miR-378a-3p, miR-146a-5p and miR-381) and tumor progression (miR-378a-3p, miR-146a-5p, miR-381, miR-223-3p, miR-494-3p, miR-940, miR-433, miR-522 and miR-637). The goal of this work was to elucidate CtBP1 and MeS effect on miRNAs expression and to investigate its function in BrCa.We studied miRNA expression levels by RT-qPCR stem loop methodology of selected miRNAs from our previous results, in CtBP1-depleted or control MDA-MB-231 xenografts generated in mice with MeS or control .We found that CtBP1 modulated miR-381-5p, miR-378a-3p, miR-146a-5p, let-7e-3p and miR-194-5p in BrCa xenografts while MeS induced miR-381-5p and miR-194-5p. By gene ontology analysis based in the bioinformatic tool ChemiRs, we determined that CtBP1/MeS associated-miRNAs are involved in cancer, apoptosis, focal adhesion and mesenchymal cell proliferation. Finally, we assessed genetic alterations in BrCa patients obtained from cBioPortal datasets. Interestingly, 1.5% of patients presented DNA amplifications in let-7e and 20% in miR-194-5p.Thus, let-7e-3p and miR-194-5p emerge as CtBP1 controlled miRNAs that might be relevant in a subset of BrCa patients with MeS.