LMTK3 confers chemo-resistance in breast cancer
| Autor: | Timothy O’Hanlon, Georgios Giamas, April Camilla Roslani, Thomas Simon, Kalpit Shah, Justin Stebbing, Michael Dean, Krisztina Sára Szabó, Teresa Gagliano, Franz Wendler, Swee Hung Cheah, Angeliki Ditsiou, Soo-Chin Lee, Tingting Wang, L C Lit |
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| Přispěvatelé: | National Institute for Health Research, Cancer Research UK |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
LEMUR TYROSINE KINASE-3 Cancer Research COMET ASSAY Nude Drug Resistance Ataxia Telangiectasia Mutated Proteins Docetaxel medicine.disease_cause DOUBLE-STRAND BREAKS Histones Double-Stranded Mice NEOADJUVANT CHEMOTHERAPY LMTK3 Tumor Cells Cultured Breast Cancer LMTK3 Doxorubicin DNA Breaks Double-Stranded Genetics & Heredity Cultured Kinase Protein-Serine-Threonine Kinases Tumor Cells Gene Expression Regulation Neoplastic Oncology Female Life Sciences & Biomedicine medicine.drug Biochemistry & Molecular Biology CELL LUNG-CANCER Mice Nude Antineoplastic Agents Breast Neoplasms Q0179.9 Biology Protein Serine-Threonine Kinases Chromatin remodeling Article NO 03 medical and health sciences Breast cancer Breast Cancer Genetics medicine Animals Humans Lemur tyrosine kinase 3 Doxorubicin Oncology & Carcinogenesis Molecular Biology Neoplastic Science & Technology THERAPEUTIC TARGET ACTIVATES ATM Drug Resistance Neoplasm Membrane Proteins Xenograft Model Antitumor Assays DNA Breaks Cancer 1103 Clinical Sciences Cell Biology IN-VITRO medicine.disease HISTONE H2AX 030104 developmental biology Gene Expression Regulation DNA-DAMAGE Cancer research Neoplasm Carcinogenesis 1112 Oncology And Carcinogenesis |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 |
| Popis: | 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\ud 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\ud doxorubicin differentially regulated the expression of over 700 genes depending on LMTK3 protein expression levels.\ud 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 postchemotherapy 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. |
| Databáze: | OpenAIRE |
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