Abstract 6498: Development of a rat model to study <i>ESR1</i> mutations in estrogen receptor-positive breast cancer

Abstract Estrogen receptor α (ER)-positive breast cancers constitute approximately 70% of all breast cancers and are commonly treated with surgery and endocrine adjuvant therapies. While these treatments significantly reduce mortality, resistance to endocrine therapies often emerges, leading to metastatic disease. One notable mechanism of resistance is ESR1 gene mutations, which usually alter the ligand-binding domain of ERα. To advance the understanding of ESR1 mutation-driven tumorigenesis and metastasis, an immunocompetent animal model is essential. Existing models, such as patient-derived xenografts, lack an intact immune system. However, rat mammary tumors are predominantly ER-positive, offering a unique advantage over mouse models, which typically form ER-negative tumors. Despite this, no rat models harboring ESR1 mutations currently exist. Here, we report the development of a novel ER-positive breast cancer model in rats carrying the Esr1 D538G somatic mutation, created using a CRISPR-Cas9-mediated homology-directed repair (HDR) precision genome-editing approach. The Esr1 D538G mutation is paired with a tumor-initiating Neurofibromin 1 (Nf1) loss-of-function mutation which was previously shown to establish ER-positive and estrogen-dependent rat mammary tumors. Detailed characterizations of this tumor model will be presented at the conference. This innovative platform provides an essential tool for investigating mechanisms of endocrine resistance in ER-positive breast cancer and for exploring novel therapeutic strategies to treat endocrine-resistant breast cancer. Citation Format: Lillian He, Wen Bu, Ruixin Xu, Yi Li. Development of a rat model to study ESR1 mutations in estrogen receptor-positive breast cancer [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 6498.