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.
Not all cancers are the same. There are, for example, at least five types of breast cancer. Different types of cancer can have different mutations and express different genes that determine how aggressively the tumors grow and how well they respond to different therapies. By exploiting these differences, scientists have developed therapies that target specific tumor types, and these targeted therapies have proven useful against most breast cancers.
One type of breast cancer, however, has proven hard to treat. Basal-like breast cancer grows rapidly and there are few treatment options for women with this type of cancer. One reason for this is that, unlike other forms of breast cancer, these cancers do not have the hormone receptors that are the targets of existing therapies.
Enzymes called kinases are promising alternate targets, and many kinase-inhibiting drugs can kill tumor cells in mice. Nevertheless, it has proven difficult to develop kinase inhibitors that are safe for use in humans because these drugs can also kill normal cells. To avoid this side effect, cancer researchers have been searching for a kinase that is active in cancer cells but not in normal cells.
Wang et al. tested a large collection of kinases and found that one called MELK caused tumors to grow in the mammary glands of mice. Further examination of tumor samples collected from hundreds of women in previous clinical studies revealed that MELK expression was increased in basal-like breast cancers and other breast cancer tumors that lack the usual hormone receptor targets.
When Wang et al. treated tumor cells and mice with tumors with a chemical that stops MELK working, basal-like breast cancer cells stopped multiplying and died. On the other hand, tumor cells that had the usual hormone receptors continued to multiply. To see if MELK is important in healthy mice, Wang et al. genetically engineered mice to delete the MELK gene and found that these mutant mice appear normal. The next challenge will be to test if drugs that inhibit MELK can kill basal-like breast cancer cells without having the side effect of harming normal cells.