CtBP1 and metabolic syndrome modulate cell adhesion and target multiple miRNAs in breast cancer cells

DE LUCA P; FARRÉ PL; DALTON N; MOIOLA CP; PORRETTI J; MASSILLO CL; SCALISE G; DE SIERVI A

New Orleans

Congreso; AACR Annual Meeting 2016; 2016

Breast cancer is the leading cause of cancer death among women, after skin cancers. Although genetic susceptibility clearlyinfluences cancer risk, noninheritedfactors determine most of the differences in cancer risk across populations and amongindividuals. Metabolic syndrome (MeS) increases the incidence and aggressiveness of breast cancer. Cterminalbinding protein 1(CtBP1) is a corepressorof tumor suppressor genes that is activated by low NAD+/NADH ratio. Previously, we found that both,CtBP1 and MeS modulated breast carcinogenesis and tumor growth using a MeS experimental mice model by chronically feedinganimals with high fat diet (HFD). The most severe form of breast cancer is metastatic and at this stage the disease is often fatal. Theaim of this work was to investigate CtBP1 and MeS role on cell adhesion, a key process for the establishment of metastasis. Wefound that CtBP1 protein diminished adhesion of MDAMB231breast cancer cells. More important, serum from MeS animalsdiminished breast cancer cell adhesion compared to control serum. In addition nude mice fed with CD or HFD were subcutaneouslyinjected with MDAMB231breast tumor cells with CtBP1 depleted expression or control cells. We found that CtBP1 and MeSmodulated expression of cell adhesion targets in the xenografts, such as Vimentin, Slug, ITGB4, Col17A1, FABP4 and PRSS2.Interestingly, miRNA expression profile obtained by RNA from CtBP1 depleted or control xenograft tumors hybridization toGeneChip miRNA 4.0 (Affymetrix) identified 42 CtBP1 regulated miRNAs. We found 77 predicted miRNAs target genes upand30 genes downregulatedby this set of 42 differentially expressed miRNAs, using miRecords data base. Gene ontology (GO)analysis of all these genes revealed an enrichment of localization, metabolic processes, cellular process and biological regulationcategories, among other biological functions. Examining processes within these GO functions; we found important categoriesoverrepresented, such as cell cycle, cell communication, vesiclemediatedtransport and primary metabolic process.These results clearly show that CtBP1 and MeS diminish adhesion of breast cancer cells and suggest a key role for thesecomponents in the begining of metastasis. In addition, understanding CtBP1 and MeS regulation of miRNAs could be crucial asmarkers for the prevention, follow up and treatment of breast cancer.