Co-dependency for MET and FGFR1 in basal triple-negative breast cancers

Abstract Triple-negative breast cancer (TNBC) is a heterogeneous disease that lacks both effective patient stratification strategies and therapeutic targets. Whilst elevated levels of the MET receptor tyrosine kinase are associated with TNBCs and predict poor clinical outcome, the functional role of...

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Autores principales:	Vanessa Y. C. Sung, Jennifer F. Knight, Radia M. Johnson, Yaakov E. Stern, Sadiq M. Saleh, Paul Savage, Anie Monast, Dongmei Zuo, Stéphanie Duhamel, Morag Park
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/895f8cc93c03496b8b2c201f974c2d24
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spelling	oai:doaj.org-article:895f8cc93c03496b8b2c201f974c2d242021-12-02T16:36:08ZCo-dependency for MET and FGFR1 in basal triple-negative breast cancers10.1038/s41523-021-00238-42374-4677https://doaj.org/article/895f8cc93c03496b8b2c201f974c2d242021-03-01T00:00:00Zhttps://doi.org/10.1038/s41523-021-00238-4https://doaj.org/toc/2374-4677Abstract Triple-negative breast cancer (TNBC) is a heterogeneous disease that lacks both effective patient stratification strategies and therapeutic targets. Whilst elevated levels of the MET receptor tyrosine kinase are associated with TNBCs and predict poor clinical outcome, the functional role of MET in TNBC is still poorly understood. In this study, we utilise an established Met-dependent transgenic mouse model of TNBC, human cell lines and patient-derived xenografts to investigate the role of MET in TNBC tumorigenesis. We find that in TNBCs with mesenchymal signatures, MET participates in a compensatory interplay with FGFR1 to regulate tumour-initiating cells (TICs). We demonstrate a requirement for the scaffold protein FRS2 downstream from both Met and FGFR1 and find that dual inhibition of MET and FGFR1 signalling results in TIC depletion, hindering tumour progression. Importantly, basal breast cancers that display elevated MET and FGFR1 signatures are associated with poor relapse-free survival. Our results support a role for MET and FGFR1 as potential co-targets for anti-TIC therapies in TNBC.Vanessa Y. C. SungJennifer F. KnightRadia M. JohnsonYaakov E. SternSadiq M. SalehPaul SavageAnie MonastDongmei ZuoStéphanie DuhamelMorag ParkNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Breast Cancer, Vol 7, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Vanessa Y. C. Sung Jennifer F. Knight Radia M. Johnson Yaakov E. Stern Sadiq M. Saleh Paul Savage Anie Monast Dongmei Zuo Stéphanie Duhamel Morag Park Co-dependency for MET and FGFR1 in basal triple-negative breast cancers
description	Abstract Triple-negative breast cancer (TNBC) is a heterogeneous disease that lacks both effective patient stratification strategies and therapeutic targets. Whilst elevated levels of the MET receptor tyrosine kinase are associated with TNBCs and predict poor clinical outcome, the functional role of MET in TNBC is still poorly understood. In this study, we utilise an established Met-dependent transgenic mouse model of TNBC, human cell lines and patient-derived xenografts to investigate the role of MET in TNBC tumorigenesis. We find that in TNBCs with mesenchymal signatures, MET participates in a compensatory interplay with FGFR1 to regulate tumour-initiating cells (TICs). We demonstrate a requirement for the scaffold protein FRS2 downstream from both Met and FGFR1 and find that dual inhibition of MET and FGFR1 signalling results in TIC depletion, hindering tumour progression. Importantly, basal breast cancers that display elevated MET and FGFR1 signatures are associated with poor relapse-free survival. Our results support a role for MET and FGFR1 as potential co-targets for anti-TIC therapies in TNBC.
format	article
author	Vanessa Y. C. Sung Jennifer F. Knight Radia M. Johnson Yaakov E. Stern Sadiq M. Saleh Paul Savage Anie Monast Dongmei Zuo Stéphanie Duhamel Morag Park
author_facet	Vanessa Y. C. Sung Jennifer F. Knight Radia M. Johnson Yaakov E. Stern Sadiq M. Saleh Paul Savage Anie Monast Dongmei Zuo Stéphanie Duhamel Morag Park
author_sort	Vanessa Y. C. Sung
title	Co-dependency for MET and FGFR1 in basal triple-negative breast cancers
title_short	Co-dependency for MET and FGFR1 in basal triple-negative breast cancers
title_full	Co-dependency for MET and FGFR1 in basal triple-negative breast cancers
title_fullStr	Co-dependency for MET and FGFR1 in basal triple-negative breast cancers
title_full_unstemmed	Co-dependency for MET and FGFR1 in basal triple-negative breast cancers
title_sort	co-dependency for met and fgfr1 in basal triple-negative breast cancers
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/895f8cc93c03496b8b2c201f974c2d24
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Co-dependency for MET and FGFR1 in basal triple-negative breast cancers

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