1. Cell Biology
  2. Human Biology and Medicine
Download icon

MELK is an oncogenic kinase essential for mitotic progression in basal-like breast cancer cells

  1. Yubao Wang
  2. Young-Mi Lee
  3. Lukas Baitsch
  4. Alan Huang
  5. Yi Xiang
  6. Haoxuan Tong
  7. Ana Lako
  8. Thanh Von
  9. Christine Choi
  10. Elgene Lim
  11. Junxia Min
  12. Li Li
  13. Frank Stegmeier
  14. Robert Schlegel
  15. Michael J Eck
  16. Nathanael S Gray
  17. Timothy J Mitchison
  18. Jean J Zhao  Is a corresponding author
  1. Dana-Farber Cancer Institute, United States
  2. Novartis Institutes for Biomedical Research, United States
  3. Harvard Medical School, United States
Research Article
  • Cited 46
  • Views 5,890
  • Annotations
Cite this article as: eLife 2014;3:e01763 doi: 10.7554/eLife.01763

Abstract

Despite marked advances in breast cancer therapy, basal-like breast cancer (BBC), an aggressive subtype of breast cancer usually lacking estrogen and progesterone receptors, remains difficult to treat. Here, we report the identification of MELK as a novel oncogenic kinase from an in vivo tumorigenesis screen using a kinome-wide open reading frames (ORFs) library. Analysis of clinical data reveals a high level of MELK overexpression in BBC, a feature that is largely dependent on FoxM1, a master mitotic transcription factor that is also found to be highly overexpressed in BBC. Ablation of MELK selectively impairs proliferation of basal-like, but not luminal breast cancer cells both in vitro and in vivo. Mechanistically, depletion of MELK in BBC cells induces caspase-dependent cell death, preceded by defective mitosis. Finally, we find that Melk is not required for mouse development and physiology. Together, these data indicate that MELK is a normally non-essential kinase, but is critical for BBC and thus represents a promising selective therapeutic target for the most aggressive subtype of breast cancer.

Article and author information

Author details

  1. Yubao Wang

    Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  2. Young-Mi Lee

    Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  3. Lukas Baitsch

    Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  4. Alan Huang

    Novartis Institutes for Biomedical Research, Boston, United States
    Competing interests
    No competing interests declared.
  5. Yi Xiang

    Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  6. Haoxuan Tong

    Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  7. Ana Lako

    Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  8. Thanh Von

    Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  9. Christine Choi

    Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  10. Elgene Lim

    Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  11. Junxia Min

    Novartis Institutes for Biomedical Research, Boston, United States
    Competing interests
    No competing interests declared.
  12. Li Li

    Novartis Institutes for Biomedical Research, Boston, United States
    Competing interests
    No competing interests declared.
  13. Frank Stegmeier

    Novartis Institutes for Biomedical Research, Boston, United States
    Competing interests
    No competing interests declared.
  14. Robert Schlegel

    Novartis Institutes for Biomedical Research, Boston, United States
    Competing interests
    No competing interests declared.
  15. Michael J Eck

    Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  16. Nathanael S Gray

    Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  17. Timothy J Mitchison

    Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  18. Jean J Zhao

    Dana-Farber Cancer Institute, Boston, United States
    For correspondence
    jean_zhao@dfci.harvard.edu
    Competing interests
    Jean J Zhao, YW, YL, AH, JZ are inventors on a patent based on some of the work described here. AH, JM, LL, RS, FS are employees of Novartis Pharmaceuticals. The other authors declare that no competing interests.

Ethics

Animal experimentation: This study was conducted in accordance with the animal use guidelines from the National Institutes of Health and with protocols (#02-127, #06-034) approved by the Dana-Farber Cancer Institute Animal Care and Use Committee.

Reviewing Editor

  1. Louis Staudt, National Cancer Institute, United States

Publication history

  1. Received: October 23, 2013
  2. Accepted: May 16, 2014
  3. Accepted Manuscript published: May 20, 2014 (version 1)
  4. Version of Record published: June 17, 2014 (version 2)

Copyright

© 2014, Wang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 5,890
    Page views
  • 738
    Downloads
  • 46
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, PubMed Central, Crossref.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Cancer Biology
    Ann Lin et al.
    Short Report

    The Maternal Embryonic Leucine Zipper Kinase (MELK) has been reported to be a genetic dependency in several cancer types. MELK RNAi and small-molecule inhibitors of MELK block the proliferation of various cancer cell lines, and MELK knockdown has been described as particularly effective against the highly-aggressive basal/triple-negative subtype of breast cancer. Based on these preclinical results, the MELK inhibitor OTS167 is currently being tested as a novel chemotherapy agent in several clinical trials. Here, we report that mutagenizing MELK with CRISPR/Cas9 has no effect on the fitness of basal breast cancer cell lines or cell lines from six other cancer types. Cells that harbor null mutations in MELK exhibit wild-type doubling times, cytokinesis, and anchorage-independent growth. Furthermore, MELK-knockout lines remain sensitive to OTS167, suggesting that this drug blocks cell division through an off-target mechanism. In total, our results undermine the rationale for a series of current clinical trials and provide an experimental approach for the use of CRISPR/Cas9 in preclinical target validation that can be broadly applied.