Maternal Embryonic Leucine Zipper Kinase is Associated with Metastasis in Triple-negative Breast Cancer

• Published in: Cancer research communications Vol. 3; no. 6; pp. 1078 - 1092
• Main Authors: Xie, Xuemei, Chauhan, Gaurav B., Edupuganti, Ramakrishna, Kogawa, Takahiro, Park, Jihyun, Tacam, Moises, Tan, Alex W., Mughees, Mohd, Vidhu, Fnu, Liu, Diane D., Taliaferro, Juliana M., Pitner, Mary Kathryn, Browning, Luke S., Lee, Ju-Hyeon, Bertucci, François, Shen, Yu, Wang, Jian, Ueno, Naoto T., Krishnamurthy, Savitri, Hortobagyi, Gabriel N., Tripathy, Debu, Van Laere, Steven J., Bartholomeusz, Geoffrey, Dalby, Kevin N., Bartholomeusz, Chandra
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01.06.2023
• Subjects: Animals; Breast Cancer; Carcinogenesis; Cell Proliferation - physiology; Humans; Leucine Zippers; Mice; Mice, Nude; Neoplasm Recurrence, Local; Oncogenes & Tumor Suppressors; Progression, Invasion & Metastasis; Protein Serine-Threonine Kinases - genetics; Stem Cell Biology; Triple Negative Breast Neoplasms - genetics
• ISSN: 2767-9764; 2767-9764
• DOI: 10.1158/2767-9764.CRC-22-0330

Triple-negative breast cancer (TNBC) has high relapse and metastasis rates and a high proportion of cancer stem-like cells (CSC), which possess self-renewal and tumor initiation capacity. MELK (maternal embryonic leucine zipper kinase), a protein kinase of the Snf1/AMPK kinase family, is known to promote CSC maintenance and malignant transformation. However, the role of MELK in TNBC metastasis is unknown; we sought to address this in the current study. We found that mRNA levels were higher in TNBC tumors [8.11 (3.79-10.95)] than in HR HER2 tumors [6.54 (2.90-9.26)]; 0.001]. In univariate analysis, patients with breast cancer with high- -expressing tumors had worse overall survival ( 0.001) and distant metastasis-free survival ( 0.01) than patients with low- -expressing tumors. In a multicovariate Cox regression model, high MELK expression was associated with shorter overall survival after adjusting for other baseline risk factors. MELK knockdown using siRNA or MELK inhibition using the MELK inhibitor MELK-In-17 significantly reduced invasiveness, reversed epithelial-to-mesenchymal transition, and reduced CSC self-renewal and maintenance in TNBC cells. Nude mice injected with CRISPR MELK-knockout MDA-MB-231 cells exhibited suppression of lung metastasis and improved overall survival compared with mice injected with control cells ( < 0.05). Furthermore, MELK-In-17 suppressed 4T1 tumor growth in syngeneic BALB/c mice ( < 0.001). Our findings indicate that MELK supports metastasis by promoting epithelial-to-mesenchymal transition and the CSC phenotype in TNBC. These findings indicate that MELK is a driver of aggressiveness and metastasis in TNBC.