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

doi:10.1016/j.celrep.2014.10.011

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. HilsenbeckJeffrey M. Rosen, Xiang H.F. Zhang, Chad A. Shaw, Fergus J. Couch, Thomas F. Westbrook

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1318-1332
Number of pages	15
Journal	Cell reports
Volume	9
Issue number	4
DOIs	https://doi.org/10.1016/j.celrep.2014.10.011
State	Published - Nov 20 2014

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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Karlin, K. L., Mondal, G., Hartman, J. K., Tyagi, S., Kurley, S. J., Bland, C. S., Hsu, T. Y. T., Renwick, A., Fang, J. E., Migliaccio, I., Callaway, C., Nair, A., Dominguez-Vidana, R., Nguyen, D. X., Osborne, C. K., Schiff, R., Yu-Lee, L. Y., Jung, S. Y., Edwards, D. P., ... Westbrook, T. F. (2014). The Oncogenic STP Axis Promotes Triple-Negative Breast Cancer via Degradation of the REST Tumor Suppressor. Cell reports, 9(4), 1318-1332. https://doi.org/10.1016/j.celrep.2014.10.011

Karlin, KL, Mondal, G, Hartman, JK, Tyagi, S, Kurley, SJ, Bland, CS, Hsu, TYT, Renwick, A, Fang, JE, Migliaccio, I, Callaway, C, Nair, A, Dominguez-Vidana, R, Nguyen, DX, Osborne, CK, Schiff, R, Yu-Lee, LY, Jung, SY, Edwards, DP, Hilsenbeck, SG, Rosen, JM, Zhang, XHF, Shaw, CA, Couch, FJ & Westbrook, TF 2014, 'The Oncogenic STP Axis Promotes Triple-Negative Breast Cancer via Degradation of the REST Tumor Suppressor', Cell reports, vol. 9, no. 4, pp. 1318-1332. https://doi.org/10.1016/j.celrep.2014.10.011

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title = "The Oncogenic STP Axis Promotes Triple-Negative Breast Cancer via Degradation of the REST Tumor Suppressor",

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.",

author = "Karlin, {Kristen L.} and Gourish Mondal and Hartman, {Jessica K.} and Siddhartha Tyagi and Kurley, {Sarah J.} and Bland, {Chris S.} and Hsu, {Tiffany Y.T.} and Alexander Renwick and Fang, {Justin E.} and Ilenia Migliaccio and Celetta Callaway and Amritha Nair and Rocio Dominguez-Vidana and Nguyen, {Don X.} and Osborne, {C. Kent} and Rachel Schiff and Yu-Lee, {Li Yuan} and Jung, {Sung Y.} and Edwards, {Dean P.} and Hilsenbeck, {Susan G.} and Rosen, {Jeffrey M.} and Zhang, {Xiang H.F.} and Shaw, {Chad A.} and Couch, {Fergus J.} and Westbrook, {Thomas F.}",

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AU - Karlin, Kristen L.

AU - Mondal, Gourish

AU - Hartman, Jessica K.

AU - Tyagi, Siddhartha

AU - Kurley, Sarah J.

AU - Bland, Chris S.

AU - Hsu, Tiffany Y.T.

AU - Renwick, Alexander

AU - Fang, Justin E.

AU - Migliaccio, Ilenia

AU - Callaway, Celetta

AU - Nair, Amritha

AU - Dominguez-Vidana, Rocio

AU - Nguyen, Don X.

AU - Osborne, C. Kent

AU - Schiff, Rachel

AU - Yu-Lee, Li Yuan

AU - Jung, Sung Y.

AU - Edwards, Dean P.

AU - Hilsenbeck, Susan G.

AU - Rosen, Jeffrey M.

AU - Zhang, Xiang H.F.

AU - Shaw, Chad A.

AU - Couch, Fergus J.

AU - Westbrook, Thomas F.

PY - 2014/11/20

Y1 - 2014/11/20

N2 - 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.

AB - 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.

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The Oncogenic STP Axis Promotes Triple-Negative Breast Cancer via Degradation of the REST Tumor Suppressor

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