The MSP‐RON axis stimulates cancer cell growth in models of triple negative breast cancer
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...
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doaj-1bd5d6c4e71a47f29ed8742bf973a8172020-11-25T03:54:28ZengWileyMolecular Oncology1574-78911878-02612020-08-011481868188010.1002/1878-0261.12734The MSP‐RON axis stimulates cancer cell growth in models of triple negative breast cancerRhona Millar0Anna Kilbey1Sarah‐Jane Remak2Tesa M. Severson3Sandeep Dhayade4Emma Sandilands5Kyla Foster6David M. Bryant7Karen Blyth8Seth B. Coffelt9Institute of Cancer Sciences University of Glasgow Glasgow UKInstitute of Cancer Sciences University of Glasgow Glasgow UKInstitute of Cancer Sciences University of Glasgow Glasgow UKDivision of Oncogenesis Netherlands Cancer Institute Amsterdam The NetherlandsCancer Research UK Beatson Institute Glasgow UKInstitute of Cancer Sciences University of Glasgow Glasgow UKInstitute of Cancer Sciences University of Glasgow Glasgow UKInstitute of Cancer Sciences University of Glasgow Glasgow UKInstitute of Cancer Sciences University of Glasgow Glasgow UKInstitute of Cancer Sciences University of Glasgow Glasgow UKTriple‐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;Brca1F/F;Trp53F/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.https://doi.org/10.1002/1878-0261.12734breast cancermouse modelsMSPMST1RRONtherapeutic target |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Rhona Millar Anna Kilbey Sarah‐Jane Remak Tesa M. Severson Sandeep Dhayade Emma Sandilands Kyla Foster David M. Bryant Karen Blyth Seth B. Coffelt |
spellingShingle |
Rhona Millar Anna Kilbey Sarah‐Jane Remak Tesa M. Severson Sandeep Dhayade Emma Sandilands Kyla Foster David M. Bryant Karen Blyth Seth B. Coffelt The MSP‐RON axis stimulates cancer cell growth in models of triple negative breast cancer Molecular Oncology breast cancer mouse models MSP MST1R RON therapeutic target |
author_facet |
Rhona Millar Anna Kilbey Sarah‐Jane Remak Tesa M. Severson Sandeep Dhayade Emma Sandilands Kyla Foster David M. Bryant Karen Blyth Seth B. Coffelt |
author_sort |
Rhona Millar |
title |
The MSP‐RON axis stimulates cancer cell growth in models of triple negative breast cancer |
title_short |
The MSP‐RON axis stimulates cancer cell growth in models of triple negative breast cancer |
title_full |
The MSP‐RON axis stimulates cancer cell growth in models of triple negative breast cancer |
title_fullStr |
The MSP‐RON axis stimulates cancer cell growth in models of triple negative breast cancer |
title_full_unstemmed |
The MSP‐RON axis stimulates cancer cell growth in models of triple negative breast cancer |
title_sort |
msp‐ron axis stimulates cancer cell growth in models of triple negative breast cancer |
publisher |
Wiley |
series |
Molecular Oncology |
issn |
1574-7891 1878-0261 |
publishDate |
2020-08-01 |
description |
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;Brca1F/F;Trp53F/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. |
topic |
breast cancer mouse models MSP MST1R RON therapeutic target |
url |
https://doi.org/10.1002/1878-0261.12734 |
work_keys_str_mv |
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