Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
Cancer Research UK Beatson Institute, Glasgow, UK.
Mol Oncol. 2020 Aug;14(8):1868-1880. doi: 10.1002/1878-0261.12734. Epub 2020 Jun 17.
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with poor prognosis and high rates of relapse. The lack of actionable targets for TNBC has contributed to the high mortality rates of this disease, and new candidate molecules for potential manipulation are urgently required. Here, we show that macrophage-stimulating protein (MSP) and its tyrosine kinase receptor, Recepteur d'origine nantais (RON), are potent drivers of cancer cell growth and tumor progression in a mouse model of TNBC driven by the loss of Trp53 and Brca1. After comparison of two genetically engineered mouse models of TNBC, we found that mammary tumors from K14-Cre;Brca1 ;Trp53 (KB1P) mice exhibit high endogenous levels of MSP and RON expression. We show that MSP stimulates serine/threonine kinase 1 and extracellular regulated MAPK activation as well as cancer cell growth in cell lines derived from the two mouse models, while genetic and pharmacological inhibition of RON prevents these effects. Similarly, KB1P tumor progression in mice was robustly attenuated by treatment with a RON inhibitor with accompanied reduction in the proliferation marker, Ki-67. Analysis of human gene expression data confirmed that the genes encoding MSP and RON are robustly expressed in human TNBC as well as other subsets of breast cancer. Our findings uncover a mouse model where MSP expression and RON expression are naturally increased, and they provide evidence that this receptor and its ligand are viable candidate molecules for targeted treatment of breast cancer.
三阴性乳腺癌（TNBC）是最具侵袭性的乳腺癌亚型，预后不良，复发率高。TNBC 缺乏可操作的靶点导致了这种疾病的高死亡率，迫切需要新的候选分子来进行潜在的操作。在这里，我们表明巨噬细胞刺激蛋白（MSP）及其酪氨酸激酶受体，Recepteur d'origine nantais（RON），是 Trp53 和 Brca1 缺失驱动的 TNBC 小鼠模型中癌细胞生长和肿瘤进展的强大驱动因素。在比较两种 TNBC 的基因工程小鼠模型后，我们发现 K14-Cre；Brca1；Trp53（KB1P）小鼠的乳腺肿瘤表现出高水平的内源性 MSP 和 RON 表达。我们表明 MSP 刺激丝氨酸/苏氨酸激酶 1 和细胞外调节 MAPK 激活以及两种小鼠模型来源的癌细胞生长，而 RON 的遗传和药理学抑制可防止这些效应。同样，用 RON 抑制剂治疗可显著减弱 KB1P 小鼠的肿瘤进展，同时伴随着增殖标志物 Ki-67 的减少。对人类基因表达数据的分析证实，编码 MSP 和 RON 的基因在人类 TNBC 以及其他乳腺癌亚群中也有强烈表达。我们的研究结果揭示了一种小鼠模型，其中 MSP 表达和 RON 表达自然增加，并提供了证据表明该受体及其配体是针对乳腺癌进行靶向治疗的可行候选分子。
