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

Xuemei Xie, Gaurav B Chauhan, Ramakrishna Edupuganti, Takahiro Kogawa, Jihyun Park, Moises Tacam, Alex W Tan, Mohd Mughees, Fnu Vidhu, Diane D Liu, Juliana M Taliaferro, Mary Kathryn Pitner, Luke S Browning, Ju-Hyeon Lee, Yu Shen, Jian Wang, Naoto T Ueno, Savitri Krishnamurthy, Gabriel N Hortobagyi, Debu TripathySteven J Van Laere, Geoffrey Bartholomeusz, Kevin N Dalby, Chandra Bartholomeusz

Research output: Contribution to journalArticlepeer-review

Abstract

UNLABELLED: 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 MELK mRNA levels were higher in TNBC tumors [8.11 (3.79-10.95)] than in HR+HER2- tumors [6.54 (2.90-9.26)]; P < 0.001]. In univariate analysis, patients with breast cancer with high-MELK-expressing tumors had worse overall survival (P < 0.001) and distant metastasis-free survival (P < 0.01) than patients with low-MELK-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 (P < 0.05). Furthermore, MELK-In-17 suppressed 4T1 tumor growth in syngeneic BALB/c mice (P < 0.001). Our findings indicate that MELK supports metastasis by promoting epithelial-to-mesenchymal transition and the CSC phenotype in TNBC.

SIGNIFICANCE: These findings indicate that MELK is a driver of aggressiveness and metastasis in TNBC.

Original languageEnglish (US)
Pages (from-to)1078-1092
Number of pages15
JournalCancer Research Communications
Volume3
Issue number6
DOIs
StatePublished - Jun 2023

Keywords

  • Humans
  • Animals
  • Mice
  • Triple Negative Breast Neoplasms/genetics
  • Mice, Nude
  • Leucine Zippers
  • Cell Proliferation/physiology
  • Neoplasm Recurrence, Local
  • Protein Serine-Threonine Kinases/genetics

MD Anderson CCSG core facilities

  • Biostatistics Resource Group

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