CTBP1 protein and metabolic syndrome impact on miRNAs expression profile associated to breast cancer.

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

C.A.B.A.

Congreso; Reunión conjunta de sociedades de biociencias; 2017

Sociedad Argentina de Investigación Clínica

Abstract: Breast cancer (BrCa) is the main cause of cancer deathin women and metabolic syndrome (MeS) increases the incidenceand aggressiveness of this disease. C-terminal Binding Protein(CtBP1) is a corepressor of tumor suppressors activated by the lowNAD+/NADH ratio. Previously, we generated a murine MeS modelby chronically feeding animals with high fat diet. We found thatCtBP1 and MeS induced BrCa growth and progression. Using microarraytechnology we showed that CtBP1 hyperactivation by MeSregulated the expression of multiple miRNAs in BrCa xenografts.Bioinformatic analysis using miRSystem resource allowed us toidentify 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 wasto elucidate CtBP1 and MeS effect on miRNAs expression and toinvestigate its function in BrCa.We studied miRNA expression levels by RT-qPCR stem loopmethodology of selected miRNAs from our previous results, inCtBP1-depleted or control MDA-MB-231 xenografts generated inmice 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 inBrCa 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 involvedin cancer, apoptosis, focal adhesion and mesenchymal cell proliferation.Finally, we assessed genetic alterations in BrCa patientsobtained from cBioPortal datasets. Interestingly, 1.5% of patientspresented DNA amplifications in let-7e and 20% in miR-194.Thus, let-7e-3p and miR-194-5p emerge as CtBP1 controlled miRNAsthat might be relevant in a subset of BrCa patients with MeS.