miRNAs expression profile induced by CtBP1 protein is critical for tumor growth and progression of breast cancer associated to metabolic syndrome.

DUCA RB; FARRÉ PL; DALTON N; PORRETTI J; SCALISE G; MASSILLO CL; BERARDINO B; DE SIERVI A; DE LUCA P

Mar del Plata

Congreso; LXI Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica; 2016

Sociedad Argentina de Investigación Clínica

Breast cancer (BrCa) is the leading cause of cancer death in women and metabolicsyndrome (MeS) constitutes a risk factor for this disease. Cterminal binding protein 1 (CtBP1) is a corepressor of tumor suppressors activated by low NAD/NADH ratio. Recently, we generated a MeSlike experimental model by chronically feeding mice with high fat diet. We found that CtBP1 and MeS inducedbreast carcinogenesis and tumor growth. Since miRNAs function as master regulators of cellular processes, the aim of this work was to identify the miRNA expression profile associated to BrCa in MeS mice. GeneChip miRNA 4.0 (Affymetrix) was hybridized to RNA from CtBP1depleted or control MDAMB231 xenografts generated in MeS mice. After data normalization, we identified 42 CtBP1 regulated miRNAs. Gene ontology analysis of miRNAs predicted target genes determined using the bioinformatic tool ChemiRs, revealed enrichment in severalbiological processes, such as fatty acid biosynthetic process, cell cycle, cellmigration and epithelial to mesenchymal transition. Furthermore using miRSystemtool we identified several CtBP1 regulated miRNAs involved in tumor growth (miR3813p, miR146a5p and miR378a3p) and tumor progression (miR2233p, miR146a5p,miR4943p, miR3813p, miR4333p, miR5223p,miR940, miR378a3p). To validate these results we assessed miRNAs expression levels in CtBP1 depleted or control MDAMB231 xenografts by miRNA RTqPCR. CtBP1 induced miR146a5p and let7e3p expression while repressed the expression of miR378a3p. Finally, we also generated 4T1 derived allografts in Balb/c mice with MeS or control, and miRNAs expression in tumor samples analyzed by miRNA RTqPCR showed that MeS induced miR378a3p, miR146a5p and let7e3p. These results show that both, CtBP1 and MeS, drives miRNAs expression which might be helpful as biomarkers for diagnosis, management and therapy of BrCa patients.