Abstract LB058: Investigating the role of SIM2 and SIRT3 in mitochondrial dynamics and homeostasis in ER+ breast cancer

Mitochondrial dynamics are essential for cellular energy regulation and homeostasis, processes crucial for normal development and breast cancer progression. Maintaining mitochondrial integrity requires a balance between fusion and fission events, which influence cellular metabolism and oxidative stress responses. Recent studies have identified Singleminded-2s (SIM2s), a tumor suppressor in mammary epithelial cells, as a regulator of mitochondrial morphology and dynamics. Our data suggest that the loss of SIM2s in estrogen receptor-positive (ER+) breast cancer cells leads to altered mitochondrial morphology, with decreased mitochondrial fusion (OPA1) and increased fission (DRP1). Additionally, SIM2 loss correlates with increased acetylation of Superoxide Dismutase 2 (SOD2) at lysine residues 68 and 122, indicating reduced SIRT3 activity. These findings suggest an interaction between SIM2 and SIRT3 in regulating mitochondrial dynamics and homeostasis. Furthermore, pharmacological inhibition of SIRT3 in SIM2-deficient cells induces synthetic lethality, highlighting SIRT3 as a potential therapeutic target for metastatic breast cancer. These results emphasize a potential relationship between SIM2 and SIRT3 and their crucial roles in mitochondrial integrity and homeostasis in ER+ breast cancer. Citation Format: Hannah N. Carter, Steven W. Wall, Garhett L. Wyatt, Lilia Sanchez, Weston W. Porter. Investigating the role of SIM2 and SIRT3 in mitochondrial dynamics and homeostasis in ER+ breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2): nr LB058.