Upregulation of MLK4 promotes migratory and invasive potential of breast cancer cells

  • Oncogene. 2019 Apr;38(15):2860-2875. doi: 10.1038/s41388-018-0618-0.
Anna A Marusiak  1 ,  Monika K Prelowska  2  3 ,  Dawid Mehlich  2  4 ,  Michal Lazniewski  5  6 ,  Klaudia Kaminska  2 ,  Adam Gorczynski  7 ,  Aleksandra Korwat  7 ,  Olga Sokolowska  2  3  8 ,  Hanna Kedzierska  2 ,  Jakub Golab  8  9 ,  Wojciech Biernat  7 ,  Dariusz Plewczynski  5  10 ,  John Brognard  11 ,  Dominika Nowis  2  4  8
Affiliations
  • 1. Laboratory of Experimental Medicine, Centre of New Technologies, University of Warsaw, Warsaw, Poland. [email protected].
  • 2. Laboratory of Experimental Medicine, Centre of New Technologies, University of Warsaw, Warsaw, Poland.
  • 3. Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland.
  • 4. Genomic Medicine, Medical University of Warsaw, Warsaw, Poland.
  • 5. Laboratory of Functional and Structural Genomics, Centre of New Technologies, University of Warsaw, Warsaw, Poland.
  • 6. Department of Physical Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Warsaw, Poland.
  • 7. Department of Pathomorphology, Medical University of Gdansk, Gdańsk, Poland.
  • 8. Department of Immunology, Medical University o``f Warsaw, Warsaw, Poland.
  • 9. Centre for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland.
  • 10. Faculty of Mathematics and Information Science, Warsaw University of Technology, Warsaw, Poland.
  • 11. National Cancer Institute, Frederick, MD, USA.
PMID: 30552384 DOI: 10.1038/s41388-018-0618-0
Abstract

Metastasis to distant organs is a major cause for solid Cancer mortality, and the acquisition of migratory and invasive phenotype is a key factor in initiation of malignancy. In this study we investigated the contribution of Mixed-Lineage Kinase 4 (MLK4) to aggressive phenotype of Breast Cancer cells. Our TCGA Cancer genomic data analysis revealed that amplification or mRNA upregulation of MLK4 occurred in 23% of invasive breast carcinoma cases. To find the association between MLK4 expression and the specific subtype of Breast Cancer, we performed a transcriptomic analysis of multiple datasets, which showed that MLK4 is highly expressed in Triple-Negative Breast Cancer compared to other molecular subtypes. Depletion of MLK4 in cell lines with high MLK4 expression impaired proliferation and anchorage-dependent colony formation. Moreover, silencing of MLK4 expression significantly reduced the migratory potential and invasiveness of Breast Cancer cells as well as the number of spheroids formed in 3D cultures. These in vitro findings translate into slower rate of tumor growth in mice upon MLK4 knock-down. Furthermore, we established that MLK4 activates NF-κB signaling and promotes a mesenchymal phenotype in Breast Cancer cells. Immunohistochemical staining of samples obtained from Breast Cancer patients revealed a strong positive correlation between high expression of MLK4 and metastatic potential of Tumors, which was predominantly observed in TNBC subgroup. Taken together, our results show that high expression of MLK4 promotes migratory and invasive phenotype of Breast Cancer and may represent a novel target for Anticancer treatment.