posted on 2024-01-29, 07:40authored byXuemei 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, François Bertucci, Yu Shen, Jian Wang, Naoto T. Ueno, Savitri Krishnamurthy, Gabriel N. Hortobagyi, Debu Tripathy, Steven J. Van Laere, Geoffrey Bartholomeusz, Kevin N. Dalby, Chandra Bartholomeusz
Clinical relevance of MELK in breast cancer and expression of MELK in breast cancer cell lines. A,MELK mRNA levels in HR−HER2+, HR+HER2−, HR+HER2+, and TNBC tumors in the World Consortium IBC dataset, analyzed by multiple comparison using a general linear model. Data are presented as mean ± SD. – represents median, X represents mean. B, IHC images (200× magnification) showing MELK protein expression in normal epithelial tissue and luminal, HER2+, and TNBC breast tumors. Correlation between MELK mRNA levels (<7 or ≥7) and OS, PFS, and DMFS in patients in the overall cohort (C) and among those with TNBC (D), determined by the Kaplan–Meier method. MELK mRNA levels (E) and protein levels (F) in TNBC and non-TNBC cells. Inset, correlation between MELK mRNA and protein levels in TNBC cell lines. In F, α-tubulin was used as a loading control. MELK mRNA levels were determined using quantitative reverse transcriptase PCR.
Funding
UT | University of Texas MD Anderson Cancer Center (MD Anderson)
Cancer Prevention and Research Institute of Texas (CPRIT)
HHS | National Institutes of Health (NIH)
History
ARTICLE ABSTRACT
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.
These findings indicate that MELK is a driver of aggressiveness and metastasis in TNBC.
