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

DALTON, GN; MASSILLO, C; DE LUCA, P; MOIOLA, CP; FARRÉ, PL; SCALISE, G; PORRETTI, J; DE SIERVI, A

Nueva Orleans

Congreso; AACR 107th Annual Meeting; 2016

American Association for Cancer Research

Breast cancer is the leading cause of cancer death among women, after skin cancers. Although genetic susceptibility clearly influences cancer risk, non-inherited factors determine most of the differences in cancer risk across populations and among individuals. Metabolic syndrome (MeS) increases the incidence and aggressiveness of breast cancer. C-terminal binding protein 1 (CtBP1) is a co-repressor of 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 feeding animals with high fat diet (HFD). The most severe form of breast cancer is metastatic and at this stage the disease is often fatal. The aim of this work was to investigate CtBP1 and MeS role on cell adhesion, a key process for the establishment of metastasis. We found that CtBP1 protein diminished adhesion of MDA-MB-231 breast cancer cells. More important, serum from MeS animals diminished breast cancer cell adhesion compared to control serum. In addition nude mice fed with CD or HFD were subcutaneously injected with MDA-MB-231 breast tumor cells with CtBP1 depleted expression or control cells. We found that CtBP1 and MeS modulated 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 to GeneChip miRNA 4.0 (Affymetrix) identified 42 CtBP1 regulated miRNAs. We found 77 predicted miRNAs target genes up- and 30 genes down-regulated by 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 regulation categories, among other biological functions. Examining processes within these GO functions; we found important categories overrepresented, such as cell cycle, cell communication, vesicle-mediated transport and primary metabolic process.These results clearly show that CtBP1 and MeS diminish adhesion of breast cancer cells and suggest a key role for these components in the begining of metastasis. In addition, understanding CtBP1 and MeS regulation of miRNAs could be crucial as markers for the prevention, follow up and treatment of breast cancer.