CtBP1 and metabolic syndrome induce breast cancer tumor progression and metastasis

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

Mar del Plata

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

Sociedad Argentina de Investigación Clínica, Sociedad Argentina de Inmunología, Sociedad Argentina de Farmacología Experimental, Sociedad Argentina de Nanomedicina y Asociación Argentina de Ciencia y Tecnología de Animales de Laboratorio

Breast cancer (BrCa) is a main worldwide public health problem. Metabolic syndrome (MeS) increases the incidence and aggressiveness of BrCa. C-terminal binding protein 1 (CtBP1) is a co-repressor of tumor suppressor genes that is activated by low NAD+/NADH ratio. Recently, we found that CtBP1 and MeS induced breast 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 the beginning 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 fed animals, were injected with CtBP1-depleted expression or -control MDA-MB-231 cells. Six weeks post-injection primary tumors were excised by surgery and, 2 weeks later, mice were sacrificed. Consistently with the onset of metastasis, MeS increased the number of mice that developed ascites (20% in MeS vs. 50% 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.