INTRODUCTION: Breast cancer accounts for nearly 40,000 deaths annually with the overall prognosis worsened if the patient is obese. Reprogramming of lipid metabolism in cancer is an established hallmark and contributes to tumorigenesis and drug-resistance. The fatty acid synthase enzyme (FASN) is overexpressed in multiple solid and hematopoietic tumors and its expression is associated with tumor grade as well as resistance to therapy. Targeted therapies against the fatty acid synthase enzyme (FASN) are currently in phase II of clinical trials for the treatment of multiple solid tumors. Previously, our lab has shown enhanced expression of FASN in breast cancer cells exposed to obese sera as well as increased sensitivity to the FASN inhibitor, TVB-3166. The obese phenotype is characterized by increased circulating bioactive growth factors and hormones, such as insulin, estrogen, and insulin-like growth factor 1 (IGF-1), that are ligands for the insulin (IR) and insulin-like growth factor receptor-1 (IGF-1R). Activation of these receptors can lead to downstream signaling through the PI3K-Akt-mTOR pathway that mediates lipogenic gene expression through various transcription factors. Of these transcription factors, sterol regulatory element-binding protein-1 (SREBP-1), drives FASN gene expression and is activated downstream of both Akt and mTORC1. HYPOTHESIS: We hypothesize that obesity-induced breast cancer progression is mediated through an SREBP dependent overexpression of FASN. METHODS: MCF-7 cells were exposed to obese or non-obese sera and subjected to quantitative RT-PCR for FASN expression. MTT and colony-forming assays using both MCF-7 and T-47D breast cancer cells conditioned in 2% obese and 2% non-obese sera as well as treated with and without a FASN inhibitor (TVB-3166) were utilized to determine cell survival and viability in response to FASN inhibition. FASN expression in obesity-induced breast cancer was investigated by treating MCF-7 cells with either insulin or SREBP processing inhibitor (Betulin) and subjected to chIP-qPCR against anti-SREBP or normal rabbit IgG. RESULTS: In response to obese sera exposure, there was a nearly 3-fold increase (p=.010) in FASN expression compared to non -obese control. Obese sera exposure increased sensitivity and decrease cell viability to TVB-3166 treatment compared to non-obese sera. ChIP-qPCR against anti-SREBP showed an increase in FASN expression upon treatment with insulin compared to normal rabbit IgG control. This increase in FASN expression was attenuated upon treatment with the SREBP processing inhibitor, Betulin. CONCLUSION: The overexpression of FASN contributes to obesity-induced breast cancer aggression and is regulated by an insulin-SREBP-FASN signaling axis.
Citation Format: Bryan Mcclellan, Tommy Pham, Brittany Harlow, Gabby Lee, Duan Quach, Christopher Jolly, Andrew Brenner, Linda deGraffenried. Fatty acid synthase enzyme as a mediator of obesity-induced breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS19-22.