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Cell Rep. 2014 Nov 20;9(4):1318-32. doi: 10.1016/j.celrep.2014.10.011. Epub 2014 Nov 6.

The oncogenic STP axis promotes triple-negative breast cancer via degradation of the REST tumor suppressor.

Author information

1
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Integrative Molecular and Biomedical Sciences Program, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
2
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
3
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
4
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
5
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
6
The Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
7
Department of Molecular and Cell Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Pathology and Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
8
Department of Pathology, Yale University School of Medicine, Yale Cancer Center, New Haven, CT 06510, USA.
9
Department of Molecular and Cell Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
10
Dan L. Duncan Cancer Center Division of Biostatistics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
11
Department of Molecular and Cell Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; The Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
12
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Integrative Molecular and Biomedical Sciences Program, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. Electronic address: thomasw@bcm.edu.

Abstract

Defining the molecular networks that drive breast cancer has led to therapeutic interventions and improved patient survival. However, the aggressive triple-negative breast cancer subtype (TNBC) remains recalcitrant to targeted therapies because its molecular etiology is poorly defined. In this study, we used a forward genetic screen to discover an oncogenic network driving human TNBC. SCYL1, TEX14, and PLK1 ("STP axis") cooperatively trigger degradation of the REST tumor suppressor protein, a frequent event in human TNBC. The STP axis induces REST degradation by phosphorylating a conserved REST phospho-degron and bridging REST interaction with the ubiquitin-ligase βTRCP. Inhibition of the STP axis leads to increased REST protein levels and impairs TNBC transformation, tumor progression, and metastasis. Expression of the STP axis correlates with low REST protein levels in human TNBCs and poor clinical outcome for TNBC patients. Our findings demonstrate that the STP-REST axis is a molecular driver of human TNBC.

PMID:
25453754
PMCID:
PMC4427000
DOI:
10.1016/j.celrep.2014.10.011
[Indexed for MEDLINE]
Free PMC Article

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