SUN-276 - SUMO1 Modulation of Antiestrogen Therapeutic Response in ER+ Breast Cancer

Breast cancer is the most commonly diagnosed cancer and second leading cause of cancer-related deaths in women worldwide. Endocrine therapies combat breast cancer by targeting estrogen receptor alpha (ERα), a ligand-dependent transcriptional regulator expressed in ~70% of tumors. Despite initial benefit, drug resistance develops in up to ~40% of ERα+ patients, often due to ESR1 ligand-binding domain mutations that enable constitutive, ligand-independent transcriptional activity. These tumors remain ER-dependent, but therapeutic mechanisms that distinguish durable from ineffective endocrine therapy response are incompletely defined. This study examines whether SUMO1 induction is a determinant of endocrine therapeutic response. Here, a novel tetrahydro-6-isoquinoline (T6I) based selective estrogen receptor modulator (SERM) engages transcriptional programs similar to the selective estrogen receptor degrader/downregulator (SERD) fulvestrant, despite contrasting effects on ERα cellular accumulation. RNA sequencing revealed that the lead compound T6I-29-1A and fulvestrant both induce small ubiquitin-like modifier-1 (SUMO1), in contrast to the pathogenic hormone 17β-estradiol. SUMOylation is a post-translational modification with broad roles in protein regulation and homeostasis, and higher SUMO1 expression has been reported to correlate with improved prognosis in ERα+ breast cancer. In patient derived ERα+ T47D cells modeling advanced metastatic disease with high levels of WT ERα, SUMO1 knockdown attenuates endocrine therapy mediated inhibition of cell proliferation and alters ERα target gene mRNA levels, particularly cell-cycle regulators. Conversely, SUMO1 overexpression enhances growth suppression by both T6I-29-1A and fulvestrant. Importantly, SUMO1 dependence is also retained in models of late-stage/metastatic disease expressing constitutively active ESR1 mutants (Y537S or D538G). Together, these findings nominate SUMO1/SUMOylation as a mechanistic determinant of endocrine therapeutic response and a potential target to improve drug efficacy in advanced ER+ breast cancer.

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