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MELK is an oncogenic kinase essential for mitotic progression in basal-like breast cancer cells
Yubao Wang1, Young-Mi Lee2, Lukas Baitsch1
1Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States.
Abstract:
Despite marked advances in breast cancer therapy, basal-like breast cancer (BBC), an aggressive subtype of breast cancer usually lacking estrogen and progesterone receptors, remains difficult to treat. In this study, we report the identification of MELK as a novel oncogenic kinase from an in vivo tumorigenesis screen using a kinome-wide open reading frames (ORFs) library. Analysis of clinical data reveals a high level of MELK overexpression in BBC, a feature that is largely dependent on FoxM1, a master mitotic transcription factor that is also found to be highly overexpressed in BBC. Ablation of MELK selectively impairs proliferation of basal-like, but not luminal breast cancer cells both in vitro and in vivo. Mechanistically, depletion of MELK in BBC cells induces caspase-dependent cell death, preceded by defective mitosis. Finally, we find that Melk is not required for mouse development and physiology. Together, these data indicate that MELK is a normally non-essential kinase, but is critical for BBC and thus represents a promising selective therapeutic target for the most aggressive subtype of breast cancer.DOI: http://dx.doi.org/10.7554/eLife.01763.001.
Insights
This study identifies MELK kinase as a key driver in basal-like breast cancer (BBC). Inhibiting MELK selectively targets BBC cells, offering a promising new therapeutic strategy for this aggressive cancer subtype.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Basal-like breast cancer (BBC) is an aggressive subtype with limited treatment options.
- Estrogen and progesterone receptor-negative status characterizes BBC.
- Novel therapeutic targets for BBC are urgently needed.
Purpose of the Study:
- To identify novel oncogenic kinases in basal-like breast cancer.
- To investigate the role of MELK (maternal embryonic leucine-rich protein kinase) in BBC proliferation and survival.
- To evaluate MELK as a potential therapeutic target for BBC.
Main Methods:
- In vivo tumorigenesis screen using a kinome-wide open reading frames (ORFs) library.
- Analysis of clinical data for MELK and FoxM1 expression in breast cancer subtypes.
- In vitro and in vivo experiments to assess the effect of MELK ablation on cancer cell proliferation.
- Investigation of the mechanistic role of MELK in cell death and mitosis.
Main Results:
- MELK was identified as a novel oncogenic kinase.
- High MELK and FoxM1 overexpression was observed in BBC, correlating with aggressive disease.
- MELK ablation selectively impaired basal-like breast cancer cell proliferation in vitro and in vivo.
- Depletion of MELK induced caspase-dependent cell death and defective mitosis in BBC cells.
- Melk is not essential for normal mouse development and physiology.
Conclusions:
- MELK is a critical oncogenic kinase overexpressed in basal-like breast cancer, driven by FoxM1.
- Selective inhibition of MELK effectively targets BBC cells, leading to cell death.
- MELK represents a promising and selective therapeutic target for aggressive basal-like breast cancer.