IRUS Total

LMTK3 confers chemo-resistance in breast cancer

File Description SizeFormat 
s41388-018-0197-0.pdfPublished version5.32 MBAdobe PDFView/Open
Title: LMTK3 confers chemo-resistance in breast cancer
Authors: Stebbing, J
Shah, K
Lit, LC
Gagliano, T
Ditsiou, A
Wang, T
Wendler, F
Simon, T
Szabó, KS
O'Hanlon, T
Dean, M
Roslani, AC
Cheah, SH
Lee, S-C
Giamas, G
Item Type: Journal Article
Abstract: Lemur tyrosine kinase 3 (LMTK3) is an oncogenic kinase that is involved in different types of cancer (breast, lung, gastric, colorectal) and biological processes including proliferation, invasion, migration, chromatin remodeling as well as innate and acquired endocrine resistance. However, the role of LMTK3 in response to cytotoxic chemotherapy has not been investigated thus far. Using both 2D and 3D tissue culture models, we found that overexpression of LMTK3 decreased the sensitivity of breast cancer cell lines to cytotoxic (doxorubicin) treatment. In a mouse model we showed that ectopic overexpression of LMTK3 decreases the efficacy of doxorubicin in reducing tumor growth. Interestingly, breast cancer cells overexpressing LMTK3 delayed the generation of double strand breaks (DSBs) after exposure to doxorubicin, as measured by the formation of γH2AX foci. This effect was at least partly mediated by decreased activity of ataxia-telangiectasia mutated kinase (ATM) as indicated by its reduced phosphorylation levels. In addition, our RNA-seq analyses showed that doxorubicin differentially regulated the expression of over 700 genes depending on LMTK3 protein expression levels. Furthermore, these genes were found to promote DNA repair, cell viability and tumorigenesis processes / pathways in LMTK3-overexpressing MCF7 cells. In human cancers, immunohistochemistry staining of LMTK3 in pre- and post-chemotherapy breast tumor pairs from four separate clinical cohorts revealed a significant increase of LMTK3 following both doxorubicin and docetaxel based chemotherapy. In aggregate, our findings show for the first time a contribution of LMTK3 in cytotoxic drug resistance in breast cancer.
Issue Date: 15-Mar-2018
Date of Acceptance: 18-Feb-2018
URI: http://hdl.handle.net/10044/1/58313
DOI: https://dx.doi.org/10.1038/s41388-018-0197-0
ISSN: 0950-9232
Publisher: Nature Publishing Group
Start Page: 3113
End Page: 3130
Journal / Book Title: Oncogene
Volume: 37
Copyright Statement: © The Author(s) 2018. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article ’ s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article ’ s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/
Sponsor/Funder: National Institute for Health Research
Cancer Research UK
Funder's Grant Number: NIHR-RP-011-053
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
Genetics & Heredity
1112 Oncology And Carcinogenesis
1103 Clinical Sciences
Oncology & Carcinogenesis
Publication Status: Published
Conference Place: England
Appears in Collections:Department of Surgery and Cancer