Abstract P3-07-10: Modulation of FASN under obese conditions

Abstract

Abstract Introduction: Obesity is known to be associated with a worse breast cancer prognosis, in part through altering metabolism in cells of the tumor microenvironment. In particular, changes in metabolism associated with fatty acid utilization have been noted in not only breast cancer, but also several other cancer types. This includes changes to both expression and activity of the Fatty Acid Synthase enzyme (FASN), which is responsible for production of long chain fatty acids, including palmitate. These changes in long chain fatty acid production can modulate tumor behavior through modulation of energy utilization such as beta-oxidation, as well as plasma membrane modulation with phospholipids. Our previous studies have demonstrated that exposure to obese conditions induces significant changes in breast cancer cell proliferation. Additionally, obesity modulates activity of other cells within the tumor microenvironment, including adipocytes, which might influence the cancer cell itself. We hypothesize one particular mechanism that supports these changes is obesity-induced upregulation of FASN and that FASN may be a viable target to limit obesity-induced progression. Methods and Results: FASN has been shown to promote cancer cell proliferation through generating fatty acid precursors required for cell proliferation, altering membrane fluidity, and activating oncogenic signaling pathways. To determine if modulation of FASN is an important mechanism by which obesity promotes disease progression, MCF-7 breast cancer cells and human pre-adipocyte cells (ASC) were exposed to 2% sera from obese postmenopausal women and 2% sera from non-obese (control) women. Preliminary quantitative PCR results demonstrated that exposure to the obese sera resulted in increased expression of FASN in both the cancer cells as well as the ASC. Current studies are on-going to determine if 1) FASN up-regulation results in increased long-chain and free fatty acid production in both the cancer and adipocyte cells, 2) whether changes in long chain and free fatty acid production results in altered metabolism and plasma membrane status and 3) whether targeting FASN with a new generation of FASN inhibitors currently being investigated in the clinic can modulate obesity-induced disease progression. Conclusions: Our findings indicate that obesity promotes upregulation of FASN in several cells within the tumor microenvironment, including adipocytes and the cancer cell itself. We have also found that using a FASN inhibitor is effective in limiting cancer cell viability and proliferation. Our on-going studies will confirm if this is an important mechanism by which obesity promotes disease progression. Since FASN inhibitors are currently being investigated in the clinic, the results of these studies will provide a better understanding of how obesity alters the biology of the disease, and may identify a novel target for improving patient outcomes. Citation Format: Pham T, Oberman A, Kim I, Lee G, Quach D, Galván G, Jolly C, Cavazos D, Brenner A, deGraffenried L. Modulation of FASN under obese conditions [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-07-10.