MELK as a Mediator of Stemness and Metastasis in Aggressive Subtypes of Breast Cancer

Triple-negative breast cancer (TNBC) is the breast cancer subtype with the poorest prognosis and lacks actionable molecular targets for treatment. Maternal embryonic leucine zipper kinase (MELK) is highly expressed in TNBC and has been implicated in poor clinical outcomes, though its mechanistic role in the aggressive biology of TNBC is poorly understood. Here, we demonstrate a role of MELK in TNBC progression and metastasis. Analysis of publicly available datasets revealed that high MELK expression correlates with worse overall survival, recurrence-free survival, and distant metastasis-free survival, and MELK is co-expressed with metastasis-related genes. Functional studies demonstrated that MELK inhibition, using genomic or pharmacologic inhibition, reduces mammosphere formation, migration, and invasion in high-MELK-expressing TNBC cell lines. Conversely, MELK overexpression in low-MELK-expressing cell lines significantly increased invasive capacity in vitro and metastatic potential in vivo, as evidenced by enhanced metastasis to the liver and lungs in a chorioallantoic membrane assay. These findings highlight MELK as a key regulator of TNBC aggressiveness and support its potential as a therapeutic target to mitigate metastasis and improve patient outcomes.