CtBP1 associates metabolic syndrome and breast carcinogenesis targeting multiple miRNAs

// Paola De Luca 1 , Guillermo N. Dalton 1 , Georgina D. Scalise 1 , Cristian P. Moiola 1 , Juliana Porretti 1 , Cintia Massillo 1 , Edith Kordon 2 , Kevin Gardner 3 , Florencia Zalazar 1 , Carolina Flumian 4 , Laura Todaro 4 , Elba S. Vazquez 5 , Roberto Meiss 6 , Adriana De Siervi 1 1 Laboratorio de Oncologia Molecular y Nuevos Blancos Terapeuticos, Instituto de Biologia y Medicina Experimental (IBYME), CONICET, Buenos Aires, Argentina 2 Departamento de Fisiologia, Biologia Molecular y Celular, Facultad de Ciencias Exactas y Naturales (FCEN), Universidad de Buenos Aires (UBA), and Instituto de Fisiologia, Biologia Molecular y Neurociencias (IFIBYNE), CONICET, Buenos Aires, Argentina 3 National Cancer Institute and National Institute of Minority Health and Disparities, National Institutes of Health, Bethesda, MD, USA 4 Area de Investigacion del Instituto de Oncologia A.H. Roffo, Universidad de Buenos Aires, Buenos Aires, Argentina 5 Laboratorio de Inflamacion y Cancer, Departamento de Quimica Biologica, Facultad de Ciencias Exactas y Naturales (FCEN), Universidad de Buenos Aires (UBA), IQUIBICEN – CONICET, Buenos Aires, Argentina 6 Departamento de Patologia, Instituto de Estudios Oncologicos, Academia Nacional de Medicina, Buenos Aires, Argentina Correspondence to: Adriana De Siervi, email: adrianadesiervi@gmail.com Keywords: CtBP1, metabolic syndrome, high fat diet, breast cancer, miRNAs Received: December 22, 2015      Accepted: February 11, 2016      Published: February 25, 2016 ABSTRACT Metabolic syndrome (MeS) has been identified as a risk factor for breast cancer. C-terminal binding protein 1 (CtBP1) is a co-repressor of tumor suppressor genes that is activated by low NAD+/NADH ratio. High fat diet (HFD) increases intracellular NADH. We investigated the effect of CtBP1 hyperactivation by HFD intake on mouse breast carcinogenesis. We generated a MeS-like disease in female mice by chronically feeding animals with HFD. MeS increased postnatal mammary gland development and generated prominent duct patterns with markedly increased CtBP1 and Cyclin D1 expression. CtBP1 induced breast cancer cells proliferation. Serum from animals with MeS enriched the stem-like/progenitor cell population from breast cancer cells. CtBP1 increased breast tumor growth in MeS mice modulating multiple genes and miRNA expression implicated in cell proliferation, progenitor cells phenotype, epithelial to mesenchymal transition, mammary development and cell communication in the xenografts. These results define a novel function for CtBP1 in breast carcinogenesis.