The MSP-RON axis stimulates cancer cell growth in models of triple negative breast cancer

Millar, R., Kilbey, A., Remak, S.-J., Severson, T. M., Dhayade, S., Sandilands, E., Foster, K., Bryant, D. M. , Blyth, K. and Coffelt, S. B. (2020) The MSP-RON axis stimulates cancer cell growth in models of triple negative breast cancer. Molecular Oncology, 14(8), pp. 1868-1880. (doi: 10.1002/1878-0261.12734) (PMID:32484599) (PMCID:PMC7400785)

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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, 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 AKT and ERK1/2 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 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Remak, Sarah-Jane and Coffelt, Dr Seth and Bryant, Dr David and Blyth, Professor Karen and Sandilands, Dr Emma and Kilbey, Dr Anna and Millar, Ms Rhona
Authors: Millar, R., Kilbey, A., Remak, S.-J., Severson, T. M., Dhayade, S., Sandilands, E., Foster, K., Bryant, D. M., Blyth, K., and Coffelt, S. B.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Molecular Oncology
Publisher:Wiley
ISSN:1574-7891
ISSN (Online):1878-0261
Published Online:02 June 2020
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Molecular Oncology 14(8): 1868-1880
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
174115CRUK Centre RenewalOwen SansomCancer Research UK (CRUK)C7932/A25142CS - Beatson Institute for Cancer Research