Abstract PO5-24-05: The Metabolic and Epigenetic Contributions of Fibroblast Growth Factor Receptor-Mediated Breast Cancer Progression

Abstract

Abstract Despite recent improvements in treatment options, breast cancer remains the second leading cause of cancer-related deaths among women, with metastasis of the primary tumor accounting for most of these deaths. Signaling by fibroblast growth factor receptors (FGFRs) is active in 85% of breast cancers and results in enhanced proliferation, migration, invasion, and therapeutic resistance of tumor cells. A common feature of breast cancer is altered cholesterol metabolism including an increase in cholesterol stored intracellularly as cholesteryl esters (CEs). In breast cancer cells, high levels of CEs are associated with aggressive disease and CEs are essential for growth and migration of cancer cells. Furthermore, there is mounting evidence that modifications to metabolic pathways impact epigenetic processes including DNA methylation and histone post-translational modifications. These epigenetic changes support tumor progression and metastasis through oncogene activation and silencing of tumor suppressors. While there have been numerous studies focused on the role of metabolic and epigenetic changes in breast cancer, none have attempted to connect these altered pathways to upstream growth factor receptor pathways, such as the FGFR pathway, in cancer cells. We hypothesize that FGFR signaling promotes changes to cholesterol metabolism and epigenetic regulation which lead to breast cancer progression. To study the proposed roles of FGFR signaling, we utilized murine mammary cells of differing metastatic abilities with inducible, oncogenic FGFR1 signaling. We also included the FGFR-dependent murine mammary tumor lines 4T1 and 4T07 which demonstrate differing metastatic capabilities. Through gene expression studies, we found an FGFR-mediated increase in cholesterol metabolic processes including cholesterol storage, uptake, and synthesis. Along with this, we found an FGFR-mediated increase in CE content in our models. Interestingly, these changes were exclusive to our highly metastatic models. Additionally, we have identified FGFR-mediated changes in the expression of histone modifying enzymes in our cell lines. Many of the enzymes modified by FGFR have been previously reported to play a role in breast cancer metastasis. To further elucidate the role of enhanced cholesterol storage in breast cancer progression, we treated cells with pharmacological inhibitors of cholesterol storage. Using in vitro assays, we demonstrate that cell survival, migration, and invasion all decrease when cholesterol storage is inhibited. Again, we observe that our highly metastatic cell line models are more sensitive to this inhibition. Taken together, these data suggest a role for FGFR signaling in promoting breast cancer progression and metastasis. With further studies, this connection may inform the development of novel therapeutic strategies to combat therapeutic resistance in breast cancer. Citation Format: Jennifer Tuokkola, Lyndsay Reese, Kaylee Schwertfeger. The Metabolic and Epigenetic Contributions of Fibroblast Growth Factor Receptor-Mediated Breast Cancer Progression [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-24-05.