Format

Send to

Choose Destination
Elife. 2014 May 20;3:e01763. doi: 10.7554/eLife.01763.

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

Author information

1
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States.
2
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States.
3
Novartis Institutes for Biomedical Research, Cambridge, United States.
4
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States Harvard University, Cambridge, United States.
5
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States.
6
Department of Systems Biology, Harvard Medical School, Boston, United States.
7
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States jean_zhao@dfci.harvard.edu.

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. In this study, 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.DOI: http://dx.doi.org/10.7554/eLife.01763.001.

KEYWORDS:

FoxM1; MELK; basal-like breast cancer; targeted therapy; triple-negative breast cancer

PMID:
24844244
PMCID:
PMC4059381
DOI:
10.7554/eLife.01763
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for eLife Sciences Publications, Ltd Icon for PubMed Central
Loading ...
Support Center