Molecular Divergence Shapes Lung- and Liver-Tropic Metastasis in HER2-Positive Breast Cancer

Metastatic colonization of distant organs remains the primary cause of breast cancer specific mortality, yet the underlying mechanisms governing organ-specific tropism remain poorly understood. To better delineate the underlying mechanisms governing the establishment of successful niches in visceral organs, animal models recapitulating the pathogenesis of human breast cancer are necessary. Through in vivo selection, we established a liver-tropic HER2 ⁺ breast cancer murine model, NT2.5LV, which achieved 90% hepatic penetrance within 10 weeks. Comparative whole-genome DNA and bulk RNA sequencing of NT2.5LV, the lung-tropic counterpart NT2.5LM, and the parental primary breast tumor cell line NT2.5 revealed conserved genomic alterations, including Erbb2 amplification, and Cdkn2a/b deletion despite their distinct organ-tropic phenotypes. Transcriptomic analysis showed that NT2.5LM incorporates DNA damage-immune adaptation with homologous recombination deficiency leading to cGAS-STING pathway activation coupled with immune checkpoint remodeling, and lung-enriched integrin-mediated adhesions. Conversely, NT2.5LV activated proliferative and metabolic programs with MMP-mediated ECM remodeling suitable for the hepatic microenvironment. These organ-specific strategies were validated in two independent clinical cohorts; the MET500 and AUORA datasets. Integrated multi-omic and immunohistochemistry analyses demonstrated that NT2.5LV recapitulates key features of human HER2 ⁺ breast tumors, including HER2 overexpression. Therapeutic testing showed that NT2.5LM’s concurrent Bcl2 overexpression confers PARP inhibitor resistance despite homologous recombination deficiency, a vulnerability reversed by Bcl2 and PARP inhibition. The HER2-targeted tyrosine kinase inhibitor neratinib reduced primary and metastatic tumor burden in vivo , establishing NT2.5LV as a clinically relevant preclinical model to assess HER2-targeted therapies.