Staff View: LMTK3 confers chemo-resistance in breast cancer

LMTK3 confers chemo-resistance in breast cancer

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...

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Main Authors:	Stebbing, Justin, Shah, Kalpit, Lit, Lei Cheng, Gagliano, Teresa, Ditsiou, Angeliki, Wang, Tingting, Wendler, Franz, Simon, Thomas, Szabó, Krisztina Sára, O’Hanlon, Timothy, Dean, Michael, Roslani, April Camilla, Cheah, Swee Hung, Lee, Soo Chin, Giamas, Georgios
Format:	Article
Published:	Springer Nature 2018
Subjects:	R Medicine
Online Access:	http://eprints.um.edu.my/20613/ https://doi.org/10.1038/s41388-018-0197-0
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spelling	my.um.eprints.206132019-03-06T01:18:37Z http://eprints.um.edu.my/20613/ LMTK3 confers chemo-resistance in breast cancer Stebbing, Justin Shah, Kalpit Lit, Lei Cheng Gagliano, Teresa Ditsiou, Angeliki Wang, Tingting Wendler, Franz Simon, Thomas Szabó, Krisztina Sára O’Hanlon, Timothy Dean, Michael Roslani, April Camilla Cheah, Swee Hung Lee, Soo Chin Giamas, Georgios R Medicine 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. Springer Nature 2018 Article PeerReviewed 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 https://doi.org/10.1038/s41388-018-0197-0 doi:10.1038/s41388-018-0197-0
institution	Universiti Malaya
building	UM Library
collection	Institutional Repository
continent	Asia
country	Malaysia
content_provider	Universiti Malaya
content_source	UM Research Repository
url_provider	http://eprints.um.edu.my/
topic	R Medicine
spellingShingle	R Medicine Stebbing, Justin Shah, Kalpit Lit, Lei Cheng Gagliano, Teresa Ditsiou, Angeliki Wang, Tingting Wendler, Franz Simon, Thomas Szabó, Krisztina Sára O’Hanlon, Timothy Dean, Michael Roslani, April Camilla Cheah, Swee Hung Lee, Soo Chin Giamas, Georgios LMTK3 confers chemo-resistance in breast cancer
description	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.
format	Article
author	Stebbing, Justin Shah, Kalpit Lit, Lei Cheng Gagliano, Teresa Ditsiou, Angeliki Wang, Tingting Wendler, Franz Simon, Thomas Szabó, Krisztina Sára O’Hanlon, Timothy Dean, Michael Roslani, April Camilla Cheah, Swee Hung Lee, Soo Chin Giamas, Georgios
author_facet	Stebbing, Justin Shah, Kalpit Lit, Lei Cheng Gagliano, Teresa Ditsiou, Angeliki Wang, Tingting Wendler, Franz Simon, Thomas Szabó, Krisztina Sára O’Hanlon, Timothy Dean, Michael Roslani, April Camilla Cheah, Swee Hung Lee, Soo Chin Giamas, Georgios
author_sort	Stebbing, Justin
title	LMTK3 confers chemo-resistance in breast cancer
title_short	LMTK3 confers chemo-resistance in breast cancer
title_full	LMTK3 confers chemo-resistance in breast cancer
title_fullStr	LMTK3 confers chemo-resistance in breast cancer
title_full_unstemmed	LMTK3 confers chemo-resistance in breast cancer
title_sort	lmtk3 confers chemo-resistance in breast cancer
publisher	Springer Nature
publishDate	2018
url	http://eprints.um.edu.my/20613/ https://doi.org/10.1038/s41388-018-0197-0
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score	13.211869

LMTK3 confers chemo-resistance in breast cancer

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