MELK is an oncogenic kinase essential for mitotic progression in basal-like breast cancer cells

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

Mitotic MELK-eIF4B signaling controls protein synthesis and tumor cell survival

“…5 G and H). We previously found that MELK is selectively required by BBC, an aggressive and therapeutically recalcitrant type of breast cancer (2). Interestingly, the level of MCL1 transcript was higher in BBC than in other subtypes of breast cancer (Fig.…”

“…Similar to other established mitotic factors, such as Aurora kinases and cyclin B1, MELK demonstrates increased protein abundance during mitosis and is degraded when cells progress into G1 phase (1,2). Our recent study proposed an essential role of MELK in the mitotic progression of specific cancer cell types, with MELK knockdown resulting in multiple mitotic defects, including G2/M arrest and mitotic cell death (2). Despite these advances, there is a lack of mechanistic understanding of the role of MELK during cell division.…”

Maternal Embryonic Leucine Zipper Kinase (MELK) as a Novel Mediator and Biomarker of Radioresistance in Human Breast Cancer

“…Previous studies, however, have demonstrated that MELK may regulate other important processes, including stem cell self-renewal through control of the cell cycle (14). Likewise, MELK has been identified as a cell-cycle modulator in tumor cell lines and was recently identified as an important target for certain solid malignancies, including brain, breast, colorectal, lung, and ovarian cancers (11,15,16). MELK has been identified as an inhibitor of apoptosis by interacting with Bcl-Gl and may play a role in mammary tumor initiation (17)(18)(19).…”

“…9). MELK is an atypical member of the snf1/AMPK family of serine/threonine kinases that has also been shown to be enriched in TNBC (10,11). This family is largely associated with cell survival under conditions of environmental challenge, such as nutrient starvation (12,13).…”

MELK kinase holds promise as a new radiosensitizing target and biomarker in triple-negative breast cancer

“…In this study, the authors focus on the maternal embryonic leucine zipper kinase, or MELK, which had been previously implicated as an oncogenic kinase important for proliferation in basal-like breast cancer (10). MELK has also been shown to be important for mitosis and replicative stress in glioma stem cells (11,12), and was shown to protect glioma stem cells from radiation induced cell death (13).…”