Cell Reports (Nov 2014)
The Oncogenic STP Axis Promotes Triple-Negative Breast Cancer via Degradation of the REST Tumor Suppressor
- Kristen L. Karlin,
- Gourish Mondal,
- Jessica K. Hartman,
- Siddhartha Tyagi,
- Sarah J. Kurley,
- Chris S. Bland,
- Tiffany Y.T. Hsu,
- Alexander Renwick,
- Justin E. Fang,
- Ilenia Migliaccio,
- Celetta Callaway,
- Amritha Nair,
- Rocio Dominguez-Vidana,
- Don X. Nguyen,
- C. Kent Osborne,
- Rachel Schiff,
- Li-Yuan Yu-Lee,
- Sung Y. Jung,
- Dean P. Edwards,
- Susan G. Hilsenbeck,
- Jeffrey M. Rosen,
- Xiang H.-F. Zhang,
- Chad A. Shaw,
- Fergus J. Couch,
- Thomas F. Westbrook
Affiliations
- Kristen L. Karlin
- Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
- Gourish Mondal
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA
- Jessica K. Hartman
- Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
- Siddhartha Tyagi
- Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
- Sarah J. Kurley
- Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
- Chris S. Bland
- Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
- Tiffany Y.T. Hsu
- Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
- Alexander Renwick
- Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
- Justin E. Fang
- Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
- Ilenia Migliaccio
- The Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
- Celetta Callaway
- Department of Molecular and Cell Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
- Amritha Nair
- Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
- Rocio Dominguez-Vidana
- Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
- Don X. Nguyen
- Department of Pathology, Yale University School of Medicine, Yale Cancer Center, New Haven, CT 06510, USA
- C. Kent Osborne
- The Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
- Rachel Schiff
- The Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
- Li-Yuan Yu-Lee
- Department of Molecular and Cell Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
- Sung Y. Jung
- Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
- Dean P. Edwards
- Department of Molecular and Cell Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
- Susan G. Hilsenbeck
- Dan L. Duncan Cancer Center Division of Biostatistics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
- Jeffrey M. Rosen
- Department of Molecular and Cell Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
- Xiang H.-F. Zhang
- Department of Molecular and Cell Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
- Chad A. Shaw
- Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
- Fergus J. Couch
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA
- Thomas F. Westbrook
- Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
- DOI
- https://doi.org/10.1016/j.celrep.2014.10.011
- Journal volume & issue
-
Vol. 9,
no. 4
pp. 1318 – 1332
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.
