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Oncogene. 2018 Jun;37(23):3113-3130. doi: 10.1038/s41388-018-0197-0. Epub 2018 Mar 15.

LMTK3 confers chemo-resistance in breast cancer.

Author information

1
Department of Surgery and Cancer, Division of Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, W12 ONN, UK.
2
Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, 20892, USA.
3
Department of Physiology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia.
4
School of Life Sciences, Department of Biochemistry and Biomedicine, University of Sussex, Brighton, BN1 9QG, UK.
5
Cancer Science Institute of Singapore, Centre for Life Sciences, 28 Medical Drive, #02-15, Singapore, Singapore.
6
Cancer Genomics Research Laboratory, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research Inc., Bethesda, MD, 20892, USA.
7
Department of Surgery, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia.
8
School of Life Sciences, Department of Biochemistry and Biomedicine, University of Sussex, Brighton, BN1 9QG, UK. g.giamas@sussex.ac.uk.

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.

PMID:
29540829
PMCID:
PMC5992129
DOI:
10.1038/s41388-018-0197-0
[Indexed for MEDLINE]
Free PMC Article

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