Stebbing, Justin and Shah, Kalpit and Lit, Lei Cheng and Gagliano, Teresa and Ditsiou, Angeliki and Wang, Tingting and Wendler, Franz and Simon, Thomas and Szabó, Krisztina Sára and O’Hanlon, Timothy and Dean, Michael and Roslani, April Camilla and Cheah, Swee Hung and Lee, Soo Chin and Giamas, Georgios (2018) LMTK3 confers chemo-resistance in breast cancer. Oncogene, 37 (23). pp. 3113-3130. ISSN 0950-9232, DOI https://doi.org/10.1038/s41388-018-0197-0.
Full text not available from this repository.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.
| Item Type: | Article |
|---|---|
| Funders: | UNSPECIFIED |
| Uncontrolled Keywords: | ATM protein; doxorubicin; histone H2AX; histone H2AX gamma; Ki 67 antigen; lemur tyrosine kinase 3; protein tyrosine kinase; transcription factor; transcription factor HEY1; transcription factor Sox6; transcriptome; unclassified drug |
| Subjects: | R Medicine |
| Divisions: | Faculty of Medicine |
| Depositing User: | Ms. Juhaida Abd Rahim |
| Date Deposited: | 06 Mar 2019 01:18 |
| Last Modified: | 06 Mar 2019 01:18 |
| URI: | http://eprints.um.edu.my/id/eprint/20613 |
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