Abstract 2455: A potential FASN -IGF1R signaling loop in breast cancer

Abstract Background: The overexpression of the IGF-1R is correlated with an overall worse prognosis for breast cancer patients. IGF-1R contributes to an aggressive phenotype through its downstream signaling cascades, including the classical PI3K-Akt- mTORC1 pathway. Recent studies suggest another important target of IGF-1R regulation is the fatty acid synthase enzyme (FASN), leading to increased endogenous fatty acid synthesis. The importance of FASN activity to breast cancer progression is illustrated by the success of recent clinical trials investigating the efficacy of FASN inhibitors in refractory breast cancer. Previous studies in our lab and others have identified SREBP and SRPK2 as key IGF-1R targets regulating FASN expression. FASN expression can lead to excess palmitate, which can serve as a substrate for palmitoylation shown to aid in the membrane localization and function of various receptor tyrosine kinases, including IGF-1R. However, the role of FASN induced localization and activation of IGF-1R in breast cancer has not been investigated and is critical for a better understanding of the role of FASN in breast cancer progression. Objective: The goal of this study is to investigate a potential feedforward signaling loop between IGF-1R and FASN and its contribution to breast tumorigenesis. Methods: The impact of suppression of mTOR, SREBP, and SRPK2 on FASN gene expression in response to IGF-1 stimulation in MCF-7 and T47D ER+ breast cancer cells over a course of time was evaluated using qPCR. The role of FASN in IGF-1R stabilization and signaling was determined in MCF-7 cells pretreated with 2-bromopalmitate (2-BP, a palmitoylation inhibitor) or the FASN inhibitor, TVB-3166. Colony formation and migration assays were performed for phenotypic analysis of breast cancer cells in response to IGF-1R and SRPK2 modulation. Results: Inhibition of mTORC1 resulted in an attenuation of FASN expression in both MCF-7 and T47D cells upon IGF-1 exposure. Additionally, inhibition of palmitoylation and/or FASN resulted in a decreased stabilization and activation of IGF-1R in MCF-7 breast cancer cells. Further elucidation of specific mechanisms of post-transcriptional regulation of FASN through SRPK2 as well as effects of SRPK2 and IGF-1R inhibition on breast cancer cell migration and survival are on-going. Conclusion: The results of this study suggest that a potential mechanism of breast cancer progression is through an autoregulatory loop between IGF-1R signaling and FASN activity, which can be effectively limited using the new class of FASN inhibitors. These data support the rationale for continued clinical studies evaluating the efficacy of FASN inhibitors in breast cancers driven, at least in part, by IGF-1 signaling. Citation Format: Bryan McClellan, Brittany Harlow, Christopher Jolly, Linda deGraffenried. A potential FASN -IGF1R signaling loop in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2455.