Abstract 1160: CtBP1 is the molecular link that associates breast cancer and metabolic syndrome

Breast cancer is still one of the most important public health problems in the entire world. Obesity and metabolic syndrome (MS) increases the incidence and aggressiveness of breast cancer. C-Terminal Binding Protein (CtBP1) is a transcriptional corepressor of tumor suppressor genes and is considered a molecular sensor of cell metabolic state due to is activated in high energy conditions (high NADH). In this work we studied the effects of the activation of CtBP1 pathway by metabolic syndrome on breast tumor development and progression. We generated a murine model of MS by chronic high fat diet (HFD) administration. By histological and whole mount methods, we found that breast tissue of animals receiving HFD presented higher levels of immature adipose tissue and an increased glandular area with more generation of lateral branches and terminal end buds of mammary ducts. Breast tissue of HFD animals also showed higher expression of the proliferation markers (cyclin D1) and epithelial markers (E-cadherin). Interestingly, HFD induced CtBP1 expression in the mammary ducts. Furthermore, the number and size of mamospheres generated with LM38-LP breast cancer cells were significantly increased when cells were incubated with serum from HFD fed mice compared to the serum of animals under control diet (CD). In addition, to investigate CtBP1 role in tumor progression we performed xenografts in nude mice fed with CD or HFD by subcutaneous injecton of breast tumor cells MDA MB 231 with depleted CtBP1 expression (shRNA CtBP1) or control cells (shRNA scramble). We found that CtBP1 depletion dramatically decreased tumor growth and KI67 expression relative to control tumors. Furthermore, xenografts developed in HFD fed mice were less differentiated compared to CD. Finally, CtBP1 diminished expression tumors showed lower mesenchymal markers expression, progenitor cells markers and markers involved in mammary development. Our studies demonstrated for the first time that gene transcription regulation by CtBP1 provides an important molecular link among MS, CtBP1 function and tumor growth. Hence, these results suggest an association to understand metabolism and breast cancer. Citation Format: Paola De Luca, Nicolas Dalton, Cristian Pablo Moiola, Carolina Flumian, Georgina Scalise, Juliana Porretti, Cintia Massillo, Edith Kordon, Laura Todaro, Elba Vazquez, Roberto Meiss, Adriana De Siervi. CtBP1 is the molecular link that associates breast cancer and metabolic syndrome. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1160. doi:10.1158/1538-7445.AM2015-1160