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Cancer Cells and Metastasis / Breast Cancer Treatment Studies / HER2/EGFR in Cancer Research · Journal article
npj Breast Cancer · August 8, 2026
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This is a preclinical mechanistic study establishing murine models of HER2+ breast cancer with distinct lung- and liver-preferential metastatic phenotypes, driven by organ-specific transcriptional and metabolic programs. Validation in clinical cohorts supports the biological relevance of the model, and neratinib reduced primary tumor growth and visceral metastases in vivo, positioning NT2.5LV as a tool for preclinical assessment of HER2-targeted therapies.
Preclinical murine xenograft models with comparative genomic and transcriptomic analysis, validated in retrospective clinical cohorts. Murine HER2+ breast cancer cell lines derived from a primary tumor; validation in human clinical cohorts with HER2+ breast tumors. Intervention: Neratinib (HER2-targeted tyrosine kinase inhibitor) in murine models. Compared with: Untreated controls (implied but not explicitly stated).
NT2.5LV liver-enriched model achieved 95% hepatic penetrance within 10 weeks NT2.5LM (lung model) displayed transcriptional homologous-recombination-repair suppression and type-I interferon-stimulated gene response NT2.5LV activated proliferative and metabolic programs with MMP-mediated ECM remodeling
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This work identifies transcriptional and metabolic drivers of organ-preferential metastasis in HER2+ breast cancer and provides a preclinical platform for testing HER2-targeted therapeutics. The mechanistic insights may inform biomarker development for predicting metastatic site, but clinical applicability remains speculative pending further translational studies.
A mechanistic study establishing novel murine models of organ-preferential metastasis with supporting transcriptomic validation in clinical cohorts, but lacking clinical trial evidence of therapeutic efficacy.
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This work identifies transcriptional and metabolic drivers of organ-preferential metastasis in HER2+ breast cancer and provides a preclinical platform for testing HER2-targeted therapeutics. The mechanistic insights may inform biomarker development for predicting metastatic site, but clinical applicability remains speculative pending further translational studies.
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Abstract Metastatic colonization of distant organs remains the primary cause of breast-cancer-specific mortality, yet the underlying mechanisms governing organ-preferential colonization remain poorly understood. To better delineate the underlying mechanisms to establish successful metastatic niches, animal models recapitulating the pathogenesis of human breast cancer are necessary. Through iterative in vivo selection, we established a liver-enriched HER2 + murine breast cancer model, NT2.5LV, which achieved 95% hepatic penetrance within 10 weeks. Comparative whole-genome and bulk RNA sequencing of NT2.5LV, the lung-enriched 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-preferential phenotypes. NT2.5LM displayed transcriptional homologous-recombination-repair suppression and a type-I interferon-stimulated gene response 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 to the hepatic microenvironment. These organ-preferential strategies were validated in two independent clinical cohorts MET500 and AURORA. Integrated multi-omic and immunohistochemical analyses demonstrated that NT2.5LV recapitulates key features of human HER2 + breast tumors, including HER2 overexpression. NT2.5LM additionally exhibited a transcriptionally anti-apoptotic, BH3-primed state. The HER2-targeted tyrosine kinase inhibitor neratinib reduced primary tumor growth and the frequency of gross visceral metastases in vivo, establishing NT2.5LV as a clinically relevant preclinical model to assess HER2-targeted therapies.
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