A susceptibility gene signature for ERBB2-driven mammary tumour development and metastasis in collaborative cross mice

作者：Hui Yang, Xinzhi Wang, Adrián Blanco‐Gómez, He Li, Natalia García‐Sancha, Roberto Corchado‐Cobos, Manuel Jesús Pérez‐Baena, Alejandro Jiménez‐Navas, Pin Wang, Jamie L. Inman, Antoine M. Snijders, David W. Threadgill, Allan Balmain, Hang Chang, Jesús Pérez‐Losada, Jian‐Hua Mao · 发表于：EBioMedicine · 年份：2024 · DOI：10.1016/j.ebiom.2024.105260 · 被引用次数：10 · 研究领域：Breast Cancer Treatment Studies、Cancer Cells and Metastasis、Genetic Mapping and Diversity in Plants and Animals

BACKGROUND: Deeper insights into ERBB2-driven cancers are essential to develop new treatment approaches for ERBB2+ breast cancers (BCs). We employed the Collaborative Cross (CC) mouse model to unearth genetic factors underpinning Erbb2-driven mammary tumour development and metastasis. METHODS: 732 F1 hybrid female mice between FVB/N MMTV-Erbb2 and 30 CC strains were monitored for mammary tumour phenotypes. GWAS pinpointed SNPs that influence various tumour phenotypes. Multivariate analyses and models were used to construct the polygenic score and to develop a mouse tumour susceptibility gene signature (mTSGS), where the corresponding human ortholog was identified and designated as hTSGS. The importance and clinical value of hTSGS in human BC was evaluated using public datasets, encompassing TCGA, METABRIC, GSE96058, and I-SPY2 cohorts. The predictive power of mTSGS for response to chemotherapy was validated in vivo using genetically diverse MMTV-Erbb2 mice. FINDINGS: Distinct variances in tumour onset, multiplicity, and metastatic patterns were observed in F1-hybrid female mice between FVB/N MMTV-Erbb2 and 30 CC strains. Besides lung metastasis, liver and kidney metastases emerged in specific CC strains. GWAS identified specific SNPs significantly associated with tumour onset, multiplicity, lung metastasis, and liver metastasis. Multivariate analyses flagged SNPs in 20 genes (Stx6, Ramp1, Traf3ip1, Nckap5, Pfkfb2, Trmt1l, Rprd1b, Rer1, Sepsecs, Rhobtb1, Tsen15, Abcc3, Arid5b,...