TY - JOUR
T1 - Maternal Embryonic Leucine Zipper Kinase is Associated with Metastasis in Triple-negative Breast Cancer
AU - Xie, Xuemei
AU - Chauhan, Gaurav B
AU - Edupuganti, Ramakrishna
AU - Kogawa, Takahiro
AU - Park, Jihyun
AU - Tacam, Moises
AU - Tan, Alex W
AU - Mughees, Mohd
AU - Vidhu, Fnu
AU - Liu, Diane D
AU - Taliaferro, Juliana M
AU - Pitner, Mary Kathryn
AU - Browning, Luke S
AU - Lee, Ju-Hyeon
AU - Shen, Yu
AU - Wang, Jian
AU - Ueno, Naoto T
AU - Krishnamurthy, Savitri
AU - Hortobagyi, Gabriel N
AU - Tripathy, Debu
AU - Van Laere, Steven J
AU - Bartholomeusz, Geoffrey
AU - Dalby, Kevin N
AU - Bartholomeusz, Chandra
N1 - © 2023 The Authors; Published by the American Association for Cancer Research.
PY - 2023/6
Y1 - 2023/6
N2 - 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.
AB - 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.
KW - Humans
KW - Animals
KW - Mice
KW - Triple Negative Breast Neoplasms/genetics
KW - Mice, Nude
KW - Leucine Zippers
KW - Cell Proliferation/physiology
KW - Neoplasm Recurrence, Local
KW - Protein Serine-Threonine Kinases/genetics
U2 - 10.1158/2767-9764.CRC-22-0330
DO - 10.1158/2767-9764.CRC-22-0330
M3 - Article
C2 - 37377604
SN - 2767-9764
VL - 3
SP - 1078
EP - 1092
JO - Cancer research communications
JF - Cancer research communications
IS - 6
ER -