Dr. Jean Zhao's lab is interested in...
How kinases in general, and phosphatidylinositol 3-kinases (PI3K) in particular, control malignant transformation. The work of our laboratory integrates molecular biology, tissue engineering and novel mouse models of human cancer to study oncogenic alterations in kinases that are involved in tumor formation and metastasis. In addition to our unique genetically engineered mouse models, we have developed a number of additional experimental systems, including, synthetic human tumors, and kinome-wide libraries of activated kinases to elucidate the mechanisms by which kinases function in cancer.
Phosphatidylinositol 3-kinases (PI3Ks) are crucial coordinators of intracellular signalling in response to extracellular stimuli. Hyperactivation of PI3K signalling cascades is one of the most common events in human cancers. In this Review, we discuss recent advances in our knowledge of the roles of specific PI3K isoforms in normal and oncogenic signalling, the different ways in which PI3K can be upregulated, and the current state and future potential of targeting this pathway in the clinic.
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.
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