LAUSR

Endometrial cancer (EC) is the most prevalent gynecological cancer and the 4th most common cancer in women globally. The frequency of EC is increasing in contrast to other prevalent cancers driven by lifestyle choices and metabolic conditions. Currently, research is focused on molecular mechanisms of tumor initiation and tumor microenvironment. ZFHX3 (ATBF1), is a transcription factor that has roles in embryogenesis steroid hormone regulation. It has been identified as a tumor suppressor gene in multiple cancer types. ZFHX3 mutations have been observed in normal endometrium and reports suggest it is mutated in about 20% of EC cases. Despite these frequent mutations, very few studies fully comprehend the molecular mechanisms behind ZHFX3 inactivation and its subsequent role in initiating EC. Our study aims to find the role of ZFHX3 in initiating EC. We knocked down ZFHX3 in 12Z cells via siRNA, followed by mRNA-seq, to examine its function in the endometrial epithelium. Our preliminary data suggests that ZFHX3 regulates c-MyB, a proto-oncogene, suggesting its role as a tumor suppressor gene in EC. We performed transcriptomic analysis on endometrial cells following the knockdown of ZFHX3 and identified differential expression of cell cycle and cell adhesion-related genes, suggesting important roles for ZFHX3 in oncogenic processes. We also overexpressed ZFHX3 expression in Ishikawa cells and treated them with estrogen and progesterone. These cells were subjected to RNA-seq analysis to identify the different signaling pathways affected by the presence of progesterone. Comparing the 2 RNA-seq data, we found EGR1 to be a common gene. We also investigated the effects of ZFHX3 knockdown in the endometrial epithelium in vivo and found an increase in the Ki67 expression and endometrial gland number, indicating endometrial hyperplasia. Future studies will focus on the relation between ZFHX3 and EGR1, its subsequent signaling pathways, and elucidating its role as a tumor suppressor. Sanjeev Ganesh, Areebah Qazi, Swornalata Pukhrambam, Sophia Agrusa, Jessica Long, Katherine Gurdziel, Michael Wilson. Effect of ZFHX3 in endometrial cancer progression [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 6716.