Abstract 992: The impact of tamoxifen on autophagic and epigenetic regulation in endometrial cancer

Abstract Background: Endometrial cancer, predominantly endometrioid adenocarcinoma, ranks as the fourth most common cancer in women globally, with an increasing incidence over the last two decades. Tamoxifen, well-known for its antiestrogenic characteristics in the treatment of breast cancer, paradoxically increases the risk of endometrial cancer. Understanding this dual role of tamoxifen is crucial for optimizing breast cancer therapy while mitigating endometrial cancer risk. This study aims to elucidate the molecular alterations induced by tamoxifen in endometrial thickening and its potential to induce cancer, particularly focusing on autophagy, epithelial-mesenchymal transition (EMT), and cancer stem-like cells (CSCs). Methods: In this study, female BALB/c mice were administered tamoxifen (20 mg/ml) orally for five consecutive days. We monitored changes in EMT markers, autophagy-related genes, and stem cell markers over 1 to 5 months. Furthermore, we investigated the epigenetic modulation of key genes involved in these processes. Results: Tamoxifen treatment led to altered expression of both epithelial and mesenchymal EMT markers, autophagy-related genes (p62, LC3B, Beclin-1, mTOR, ATG12, ATG16), and stem cell markers (Nanog, SOX2, ALDH1). Notably, we observed significant epigenetic changes, including increased methylation of E-cadherin and decreased methylation of Twist. Furthermore, we observed hypermethylation (a process often linked to the silencing of tumor-suppressing genes) in MGMT (Methylguanine methyltransferase), a DNA repair enzyme involved in chemoresistance, and DAPK (Death-associated protein kinase), a kinase associated with apoptosis, autophagy, and inflammation. We also observed hypermethylation in the CpG promoter regions of autophagy-related genes (Beclin-1 and LC3B) highlighting a potential mechanism for tamoxifen-induced tumorigenic changes. Conclusion: Our findings demonstrate tamoxifen's influence on cellular and molecular pathways, highlighting the complex interplay between drug treatment and cancer progression. The observed epigenetic changes provide insight into the mechanisms by which tamoxifen may contribute to endometrial cancer risk, suggesting potential targets for therapeutic intervention. Citation Format: Shilpa Thota, Rizwana Begum, Naveen Chintala, Abhishek Pandit, Biplov Sapkota, Joseph Francis. The impact of tamoxifen on autophagic and epigenetic regulation in endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 992.