癌症研究
生物
乳腺癌
肿瘤进展
癌症
转移
转移性乳腺癌
转录组
乳腺肿瘤
下调和上调
内科学
原发性肿瘤
基因表达
医学
基因
生物化学
作者
Brian G. Hunt,James N. Davis,Levi H. Fox,Sara Vicente-Muñoz,Carissa Lester,Susanne I. Wells,Susan E. Waltz
出处
期刊:Oncogene
[Springer Nature]
日期:2023-04-07
卷期号:42 (21): 1716-1727
被引量:1
标识
DOI:10.1038/s41388-023-02688-5
摘要
Recurrence remains a significant clinical barrier to improving breast cancer patient outcomes. The RON receptor is a predictor of metastatic progression and recurrence in breast cancers of all subtypes. RON directed therapies are in development, but preclinical data directly testing the impact of RON inhibition on metastatic progression/recurrence are lacking, and mechanisms to exert this function remain unclear. Herein, we modeled breast cancer recurrence using implantation of RON-overexpressing murine breast cancer cells. Recurrent growth was examined after tumor resection via in vivo imaging and ex vivo culture of circulating tumor cells from whole blood samples from tumor bearing mice. In vitro functional assessment of was performed using mammosphere formation assays. Transcriptomic pathway enrichment identified glycolysis and cholesterol biosynthesis pathways, transcription factor targets, and signaling pathways enriched in RON-overexpressing breast cancer cells. BMS777607, a RON inhibitor, abrogated CTC colony formation tumor cells and tumor recurrence. RON promoted mammosphere formation through upregulated cholesterol production that utilizes glycolysis-derived substrates. In mouse models with RON overexpression, statin-mediated inhibition of cholesterol biosynthesis impeded metastatic progression and recurrence but does not affect the primary tumor. RON upregulates glycolysis and cholesterol biosynthesis gene expression by two pathways: MAPK-dependent c-Myc expression and β-catenin -dependent SREBP2 expression.
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