Abstract 5568: The estrogen sulfotransferase drives pancreatic ductal adenocarcinoma

Abstract Background: pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with only a 12% five-year survival rate. The complex nature of PDAC limits treatment options, highlighting the need to identify novel therapeutic targets. Males are more likely to develop PDAC than females, so we performed an initial screening of estrogen-metabolizing enzymes associated with PDAC development. Interestingly, Estrogen sulfotransferase (SULT1E1 or EST) was found to be the most over-expressed in pancreatic ductal adenocarcinoma (PDAC) compared to normal tissues, and it is associated with a poor prognosis for patients. A primary function of EST is sulfonating and deactivating estrogens. Hence, we aimed to investigate the role of EST in PDAC development and progression. Methods: Human PDAC transcriptome and proteome data were accessed from TCGA and CPTAC databases respectively. The expression pattern of EST in human PDAC tissues and genetically engineered PDAC mice model, KC (K-rasLSL.G12D/+; Pdx-1-Cre) and KPC (K-rasLSL.G12D/+; Trp53R172H/+; Pdx-1-Cre) tissues was determined using IHC and immunofluorescence. MIA PaCa-2 (KRASMT TP53MT CDKN2AHD SMAD4WT) and CFPAC-1(KRASMT TP53MT CDKN2APM SMAD4HD) cells were used to investigate the role of EST in both in vitro and in vivo models. Results: In the TCGA pan-cancer atlas, we identified that EST is over-expressed only in PDAC compared to other cancer types. Analysis of single-cell RNA sequencing data, Immunohistochemistry, and immunofluorescence studies revealed that EST is overexpressed in PDAC-specific ductal cells in human tissue, as well as in tissues from KC and KPC mice, compared to normal tissues. Overexpression of EST in MIA PaCa-2 and CFPAC-1 cells increased proliferation, migration, wound healing, and sphere formation, along with significantly less stem cell frequency. Moreover, we observed increased Ki-67 positive nuclei, elevated nuclear Cyclin D1 levels, and the upregulation of cyclin D1 target gene signatures in EST overexpressed cells. Additionally, the overexpression of EST was linked to increased tumor growth in vivo in both male and female xenograft models, highlighting EST's significant role in the progression of PDAC. Enzyme activity dead mutant EST overexpression revealed that the pro-PDAC effect of EST depends on its enzymatic activity but is independent of estrogen. Conclusion: We have uncovered a novel function of EST in the development of PDAC, and it may represent a potential target for treating PDAC. Citation Format: Syamprasad NP, Shijia S. Feng, Donovan Whitfield, Wen Xie. The estrogen sulfotransferase drives pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5568.