A new, immunocompetent brain-metastatic mouse model of HER2-positive breast cancer

Brain metastasis is a common and devastating complication of cancer that affects over 50% of HER2-positive (HER2⁺) breast cancer patients. The lack of effective long-term treatment options for brain metastasis significantly increases morbidity and mortality among these patients. Therefore, understanding the underlying mechanisms that drive brain metastasis is critically important for developing new strategies to treat it effectively. Genetically engineered mouse models (GEMMs) of HER2⁺ breast cancer have been instrumental in understanding the development and progression of HER2⁺ breast cancer. However, the GEMM models for HER2⁺ breast cancer do not develop brain metastasis and are not suitable for the study of brain metastasis. We therefore developed a fully immunocompetent mouse model of experimental brain metastasis in HER2⁺ breast cancer by injecting a murine HER2/neu-expressing mammary-tumor-cell line into the arterial circulation of syngeneic FVB/N mice followed by isolation of brain-metastatic derivatives through in-vivo selection. By this in-vivo serial passaging process, we selected highly brain-metastatic (BrM) derivatives known as neu-BrM. Notably, after intracardiac injection, neu-BrM cells generated brain metastasis in 100% of the mice, allowing us to study the later stages of metastatic progression, including cancer-cell extravasation and outgrowth in the brain. Analogous to human brain metastasis, we observed reactive gliosis and significant immune infiltration in the brain tissue of mice injected with neu-BrM cells. We further confirmed that brain-metastatic lesions in the neu-BrM model express HER2. Consistently, we found that the brain-metastatic burden in these mice can be significantly reduced but not eliminated with tucatinib, an FDA-approved, blood-brain-barrier-penetrant HER2 inhibitor. Therefore, the neu-BrM HER2⁺ breast cancer model can be used to investigate the roles of innate and adaptive immune-system components during brain-metastatic progression and the mechanisms of HER2-therapy response and resistance.