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)
|
Text
215963.pdf - Published Version Available under License Creative Commons Attribution. 3MB |
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: | Coffelt, Professor Seth and Bryant, Dr David and Blyth, Professor Karen and Sandilands, Dr Emma and Millar, Ms Rhona and Remak, Sarah-Jane and Kilbey, Dr Anna |
| 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 > School of Cancer Sciences College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
| Research Centre: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology |
| 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 |
University Staff: Request a correction | Enlighten Editors: Update this record
Funder and Project Information
Funder and Project Information