CtBP1 and metabolic syndrome induce breast cancer progression and lung metastasis

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

Washington DC

Congreso; 110 Annual Meeting 2017; 2017

Breast cancer (BrCa) is one of the most important public health problems inthe entire world. 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 generated a MeS-like experimental mice model by chronically feeding animals with high fat diet (HFD) and we found that CtBP1 and MeS modulated breast carcinogenesis and tumor growth. We also showed that CtBP1 and MeS decreased BrCa cell adhesion, a crucial event in the beginning of metastasis. Considering metastasis is still the main cause of death, and around 30 % of women with BrCa diagnosed at early stages will progress to metastatic stage, it is crucial to understand the impact of non-inherited factors and the mechanism underlying this process. The aim of this work was to explore CtBP1 and MeS rolein BrCa cell migration and metastasis. By wound healing assay, we found that CtBP1 increased cell migration of MDA-MB-231 and 4T1 BrCa cells. To studyCtBP1 and MeS effect in tumor progression, MeS nude mice induced by chronically feeding animals with HFD; and control diet fed animals, were injected with CtBP1-depleted expression or -control MDA-MB-231 cells. Six weeks post-injection primary tumors were surgically removed. After two weeks, mice were sacrifıced and the presence of metastasis in lung, liver and ascites was analyzed by histology and/or quantifıed by RT-qPCR using specifıc primers for human GAPDH. Consistently with the onset of metastasis, MeS increased the number of mice that developed neoplastic ascites (20% in MeS vs. 50% in control) withpresence of tumor cells (TC) detected by RT-qPCR. In addition, histological analysis and RT-qPCR quantitation revealed that CtBP1 hyperactivation by MeS signifıcantly increased BrCa lung metastasis. Interestingly, human Vimentin mRNA was induced in TC from ascites compared to primary TC; while it was diminished in lung, suggesting the crucial role of EMT/MET processes in metastasis. Finally, we analyzed expression of cell adhesion and EMT-related genes in primary tumor tissue by RT-qPCR.Wefound 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.