The MSP‐RON axis stimulates cancer cell growth in models of triple negative breast cancer. Issue 8 (17th June 2020)

• Record Type: Journal Article
• Authors: Millar, Rhona; Kilbey, Anna; Remak, Sarah‐Jane; Severson, Tesa M.; Dhayade, Sandeep; Sandilands, Emma; Foster, Kyla; Bryant, David M.; Blyth, Karen; Coffelt, Seth B.
• Is Part Of: Molecular oncology. Volume 14:Issue 8(2020)
• Page Start: 1868
• Page End: 1880
• Publication Date: 2020-06-17
• Subjects: breast cancer -- mouse models -- MSP -- MST1R -- RON -- therapeutic target; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1002/1878-0261.12734
• Languages: English
• ISSNs: 1574-7891

Abstract

Abstract : 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 F/F ;Trp53 F/F (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. Abstract : This study demonstrates that MSP is expressed in mammary cancer cells in the K14‐Cre;Brca1 F/F ;Trp53 F/F (KB1P) model. MSP binds the Recepteur d'origine nantais (RON) receptor, which activates serine/threonine kinase 1 and MAPK signaling to induce mammary cancer cell growth. Inhibition of the RON receptor slows KB1P cancer cell growth and progression.