MELK is an oncogenic kinase essential for mitotic progression in basal-like breast cancer cells.
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.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States.
Yubao
Y
Wang
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States.
Young-Mi
YM
Lee
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States.
Lukas
L
Baitsch
Novartis Institutes for Biomedical Research, Cambridge, United States.
Alan
A
Huang
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States.
Yi
Y
Xiang
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States.
Haoxuan
H
Tong
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States.
Ana
A
Lako
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States.
Thanh
T
Von
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States Harvard University, Cambridge, United States.
Christine
C
Choi
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States.
Elgene
E
Lim
Novartis Institutes for Biomedical Research, Cambridge, United States.
Junxia
J
Min
Novartis Institutes for Biomedical Research, Cambridge, United States.
Li
L
Li
Novartis Institutes for Biomedical Research, Cambridge, United States.
Frank
F
Stegmeier
Novartis Institutes for Biomedical Research, Cambridge, United States.
Robert
R
Schlegel
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States.
Michael J
MJ
Eck
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States.
Nathanael S
NS
Gray
Department of Systems Biology, Harvard Medical School, Boston, United States.
Timothy J
TJ
Mitchison
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.
Jean J
JJ
Zhao
D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000502:physiology*; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D020869:Gene Expression Profiling; D055786:Gene Knockout Techniques; D006801:Humans; D051379:Mice; D008938:Mitosis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D013234:Stem Cells; D014183:Transplantation, Heterologous
C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C484610:MELK protein, human; D017346:Protein Serine-Threonine Kinases
FoxM1; MELK; basal-like breast cancer; targeted therapy; triple-negative breast cancer