Abstract LB455: SUMO1: induction contributes to the efficacy of fulvestrant and T6I-29 in breast cancer cells

Abstract Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer-related deaths in women worldwide. Estrogen receptor alpha (ERα), a ligand-dependent transcriptional regulator, is overexpressed in approximately 70% of breast cancer cases, driving tumor progression. Selective estrogen receptor modulators (SERMs) and downregulators or degraders (SERDs) are therapeutic agents that manipulate ERα conformation to treat and prevent metastatic disease. Despite their clinical efficacy, resistance to these competitive allosteric regulators develops in up to ∼40% of ERα-positive breast cancer patients, even as the tumor continues to depend on ERα signaling. In this study a novel SERM based on a tetrahydro-6-isoquinoline (T6I) scaffold and optimized utilizing structure-activity relationships is found to engage transcriptional programs similar to the clinically relevant SERD fulvestrant. Specifically, transcriptomic analysis via RNA sequencing shows that our lead compound, T6I-29, and fulvestrant both induce the expression of small ubiquitin-like modifier-1 (SUMO1), in contrast to the pathogenic hormone 17β-estradiol. SUMOylation, a post-translational modification (PTM), plays a significant role in various cellular processes, including protein-protein interactions, protein stability, nuclear transport, DNA damage response, apoptosis, and transcriptional regulation. Notably, high expression of SUMO1 correlates with a better prognosis in ERα-positive breast cancer patients. This induction of SUMO1 highlights its potential role in mediating the antiestrogenic effects of these compounds. The selective accumulation of ERα observed with T6I-29 further suggests that SUMOylation may be a key modulator of the therapeutic response in antiestrogen treatments. This effect is observed using a genetic knockdown of SUMO1, which attenuates anti-proliferative efficacy of the compounds in the T47D breast cancer cell line, while also modifying the mRNA levels of ERα target genes. On the other hand, overexpression of SUMO1 enhances the antiestrogens ability to control cell growth in these cells. Furthermore, a nanoBiT assay demonstrates the presence of fulvestrant increases interaction between ERα and the SUMOylation E2 conjugating enzyme UBC9. Together, these findings emphasize the need to deepen our understanding of SUMOylation in breast cancer, including its induction, structural mechanisms, and its potential as an exploitable therapeutic target for treating advanced breast cancer. Citation Format: Govinda Hancock, Kristen Young, Sean Fanning. SUMO1: induction contributes to the efficacy of fulvestrant and T6I-29 in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB455.