SUN-295 - Modeling Estrogen Receptor Positive Breast Cancer Liver Metastasis and Fibroblast Growth Factor Receptor Driven Resistance in Rats

Estrogen receptor–positive (ER+) breast cancer accounts for over 70% of all breast cancers and is treated with endocrine therapy. However, approximately 50% of patients eventually relapse, and the five-year survival rate is 27% for metastatic ER+ disease. Endocrine therapy is often combined with CDK4/6 inhibitors, yet acquired resistance remains a significant clinical challenge.
Current genetically engineered mouse models are predominantly ER-negative, limiting their utility for studying ER+ metastatic progression. To address this gap, we developed a novel ER+ metastatic breast cancer model in immunocompetent August Copenhagen Irish (ACI) rats. Estrogen implantation in female ACI rats induces ER+ mammary tumors at 100% incidence with luminal B profiles resembling human ER+ cancers. From these tumors, we derived MG-1, an estrogen-dependent cell line sensitive to fulvestrant and CDK4/6 inhibitors. Orthotopic MG-1 injections rarely produce distant lesions, but intravenous injection efficiently yields lung, bone, lymph node, and liver metastases. Metastatic sublines show epithelial-to-mesenchymal transition signatures and increased resistance to endocrine and CDK4/6 therapies.
Liver metastasis is an underexplored complication of ER+ breast cancer with no current preclinical models. MG-1 liver-derived sublines overexpress FGFR1 and amplify FGFR2, exhibit enhanced migratory and clonogenic capacity, increased liver metastasis in vivo, and resistance to fulvestrant and CDK4/6 inhibitors. Knockdown of FGFR1 or FGFR2 partially restores drug sensitivity and suppresses metastatic traits. Given that FDA-approved FGFR inhibitors exist, this MG-1/ACI model provides a robust platform to evaluate FGFR1/2 as liver-tropic drivers and test FGFR- and CDK4/6-targeted therapies to improve outcomes for metastatic ER+ breast cancer patients.