Tumor development in breast cancer by activation of fatty acid synthase in diets rich in palmitic acid and fructose

Abstract

Breast cancer is the first leading cause of mortality in women and is associated with genetic and epigenetic factors such as dietary compounds. In our laboratory we demonstrated that dietary polyunsaturated fatty acids (PUFAs) activate enzymes such as cyclooxygenases, lipooxygenases and other peroxidases implicated in the regulation of carcinogenesis. The fatty acid synthase (FASN) is involved in de novo lipogenesis, catalyzing the synthesis of endogenous fatty acids. In early stages of carcinogenesis, the activation of this enzyme is mediated by hypoxia, which is induced by high concentrations of simple carbohydrates and fats. Its overexpression is associated with a poor prognosis, however, the dietary regulation of FASN in breast cancer development is still unknown. The aim of this study was to evaluate the variation in dietary palmitic acid (PA) and fructose (Fr) on the regulation of FASN expression mediated by hypoxia in murine breast cancer development. 

BALB/c mice (n=40) were divided in four dietary groups, CONTROL (6% corn oil+30%fructose), PCS (20% palm oil+15%fructose), PBA (20%corn oil+45%fructose) and PCS+PBA (20% palm oil+45% fructose). After 90 days mice were inoculated with murine breast adenocarcinoma LM3 cells (1x10⁶cell). In this model we evaluated tumor volume (with calimeter), lipid profile (gas chromatography: GC), FASN expression (Western Blot and immunohistochemistry) and tumor histology (H/E). For the in vitro model, cultured LM3 cells were treated with PA (40µM-50µM) and/or Fr (2.5µM) for 24hs. We evaluated viability (resazurin), apoptosis (Hoechst), lipid profile (GC), FASN expression (Western Blot). Three replicates were minimally performed by experiment and analyzed by ANOVA. 

The PCS+PBA diet produced an increment in tumor growth, infiltration, necrosis and FASN expression (p<0.05). FASN expression was increased after PA and Fr (40/2.5 µM) treatment in LM3 cells. The PCS group presented the highest percentage of PA and the PBA a high percentage of ω-6 PUFAs in membranes with respect to the other experimental groups. The combination of PA 40µM and Fr 2.5µM treatment decreased LM3 apoptotic cells and PA 40µM increased cell viability.

Diets high in palmitic acid and fructose induce tumor development in murine breast cancer, mediated by an increment in FASN enzyme expression regulated by hypoxia.