CtBP1 and metabolic syndrome induce breast cancer tumor progression and metastasis.

FARRÉ PL; DALTON N; DUCA RB; SCALISE G; MASSILLO CL; PORRETTI J; 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 a main worldwide public health problem. Metabolicsyndrome (MeS) increases the incidence and aggressiveness of BrCa. C-terminalbinding protein 1 (CtBP1) is a co-repressor of tumor suppressor genes that isactivated by low NAD+/NADH ratio. Recently, we found that CtBP1 and MeS inducedbreast carcinogenesis and tumor growth using a MeS-like mice model. We also showed that CtBP1 and MeS decreased BrCa cell adhesion, a crucial process in thebeginning of metastasis. The aim of this work was to explore CtBP1 and MeS role in BrCa cell migration and metastasis. By wound healing assay, we found that CtBP1 increased cell migration of MDA-MB-231 and 4T1 BrCa cells. MeS nude mice induced by chronically feeding animals with high fat diet and control diet, were injected with CtBP1-depleted expression or control MDA-MB-231 cells. Six weekspost-injection primary tumors were excised by surgery and, 2 weeks later, micewere sacrificed. Consistently with the onset of metastasis, MeS increased the number of mice that developed ascites (50% in MeS vs 20% in control). Tumor cells (TC) in ascites, lung and liver were detected by RT-qPCR using specific primers for human GAPDH. We found that MeS increased TC in liver. In addition, CtBP1 hyperactivation by MeS significantly increased lung metastasis. Interestingly, human Vimentin mRNA was induced in TC from ascites compared to primary TC; while it was diminished in lung. Finally, we analyzed expression of cell adhesion and EMT-related genes in primary tumor tissue by RT-qPCR. We found that CtBP1 and MeS modulated cell adhesion and EMT expression genes: Vimentin, Slug, ITGB4, ITGB6, Col17A, FABP4 and PRSS2. Altogether, these results suggest a key role for MeS and CtBP1 inducing BrCa EMT and metastasis.