Abstract 3832: Modeling metastatic ER+ breast cancer in rats

Abstract Estrogen receptor-positive (ER+) breast cancer makes up over 70% of all breast cancer and is treated with frontline endocrine therapy. However, the five-year survival rate for metastatic patients is only 27%. At this stage, patients are treated with a combination of endocrine and CDK4/6 inhibitors (e.g., palbociclib), but the development of drug resistance often arises. Genetically engineered mouse models are largely ER-negative. We developed a first-in-class ER+ metastatic breast cancer rodent model to enable a mechanistic understanding of organotropism of metastasis and the development of new treatment regimens. Following estrogen implantation in the female August Copenhagen Irish (ACI) rats, the physiological levels of estrogen are sufficient to induce ER+ mammary tumors at an incidence of 100%. RNA-sequencing revealed that rat tumors recapitulate human luminal B tumors. We subsequently derived MG-1, an ER+ rat breast cancer cell line, from ACI rat tumors. The growth of MG-1 is estrogen-dependent and inhibited by fulvestrant and CDK4/6 inhibitors. However, MG-1 does not frequently metastasize following orthotopic injection. When MG-1 cells were tail-vein injected into female ACI rats, colonization to the lung, liver, lymph nodes, and bone, all the human-relevant metastatic organs, were observed. Cells were disassociated from these tissues, flow-sorted, and cultured. Although MG-1 metastatic sublines derived from different organs exhibit distinct gene expression profiles, they all display epithelial-to-mesenchymal (EMT) signatures and are more resistant to endocrine or CDK4/6 inhibitors. In clinical trials, fibroblast growth factor receptor (FGFR) amplification/overexpression is frequently associated with endocrine and CDK4/6 inhibitor resistance. Compared with parental MG-1, MG-1 metastatic liver sublines overexpress FGFR1, elicit enhanced migration and colony formation capabilities, and are resistant to fulvestrant and CDK4/6 inhibitors. Knockdown of FGFR1 partially restored CDK4/6 inhibitor sensitivity and decreased the metastatic phenotype. Since two pan-FGFR1 inhibitors are FDA-approved for the treatment of cancers with FGFR abnormality, our immunocompetent MG-1/ACI rat model is well-suited for testing different combinations of CDK4/6 inhibitors and pan-FGFR inhibitors in treating metastatic disease. The results will inform the treatment strategy for metastatic ER+ breast cancer patients harboring FGFR alterations. We acknowledge funding support R01CA268183 to W.X. and T32 CA009135 to C. J. Citation Format: Carstyn F. Joiner, Gui Ma, Sydney Schjoneman, Patrick Colegrove, James Shull, Wei Xu. Modeling metastatic ER+ breast cancer in rats [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 3832.