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 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 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

The role of lemur tyrosine kinase 3 (LMTK3) in DNA damage repair

The lemur tyrosine kinase 3 (LMTK3) is a member of the receptor tyrosine kinase family, previously identified as an oestrogen receptor alpha regulator that involve in endocrine resistance. Importantly, LMTK3 expression has been found in colorectal cancer, non-small cell lung cancer and particularly elevated in high-grade breast cancer. Indeed, LMTK3 overexpression promotes cancer progression and regulates gene transcription of LMTK3-bound tumour suppressor-like genes. Nonetheless, the function and the molecular mechanism of this kinase to overcome drug cytotoxicity in chemotherapy, remain poorly defined. The aims of this thesis are to discover whether LMTK3 plays a role in DNA damage response to doxorubicin and elucidate its mechanism of actions. To study LMTK3 function, we generated stably overexpressed-LMTK3 cell lines. Next, we found that in doxorubicin treatment, these cell lines were more resistant as compared with its control cells. In response to doxorubicin, at the early response, the overexpression of LMTK3 reduced phosphorylation of ATM at serine 1981, which led to decrease serine 428 KAP1 and serine 139 H2AX phosphorylation. In addition, overexpressed-LMTK3 cells reduced H2AX monoubiquitination. These series of events attenuate doxorubicin-induced DNA damage, protecting cells from death. Then we demonstrated that LMTK3 facilitates homologous recombination repair rather than non-homologous end-joining repair. We determined that LMTK3 directly binds to RAD51 and maintains the RAD51 protein level. Overexpression of LMTK3 maintained RAD51 in the nuclear compartment and may recruit RAD51 to filaments which enhance the repair of damaged DNA. Our present study provides a mechanistic insight of LMTK3 role in protecting cells from doxorubicin-induced DNA damage and promoting homologous recombination repair pathway through RAD51 binding.Open Acces

LATS2 is a modulator of estrogen receptor alpha

BACKGROUND Estrogen Receptor α (ERα), a member of the nuclear receptor superfamily of transcription factors, plays a central role in breast cancer development. More than two-thirds of patients with breast cancer are ERα-positive; however, a proportion becomes resistant. Phosphorylation of ERα is one of the mechanisms associated with resistance to endocrine therapy. In a kinome screen, we have identified the large tumor suppressor homolog-2 (LATS2) as a potential kinase, acting on ERα. MATERIALS AND METHODS The role of LATS2 on activation of ERα transcription and its functional consequences was examined by various molecular and cellular biology techniques. RESULTS LATS2 co-localises with ERα in the nucleus. LATS2-silencing increases expression of ERα-regulated genes and inhibits proliferation. At the protein level, inhibition of LATS2 reduces the expression of cyclin-D1 and Nuclear Receptor Co-Repressor (NCoR) while increasing the expression of p27. CONCLUSION Identifying novel kinases which modulate ERα activity is relevant to therapeutics. LATS2 modulates ERα-regulated gene transcription, through direct and/or indirect interactions with ERα

Genetics Matters: Voyaging from the Past into the Future of Humanity and Sustainability

The understanding of how genetic information may be inherited through generations was established by Gregor Mendel in the 1860s when he developed the fundamental principles of inheritance. The science of genetics, however, began to flourish only during the mid-1940s when DNA was identified as the carrier of genetic information. The world has since then witnessed rapid development of genetic technologies, with the latest being genome-editing tools, which have revolutionized fields from medicine to agriculture. This review walks through the historical timeline of genetics research and deliberates how this discipline might furnish a sustainable future for humanity