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 | |
| State | Published - Nov 20 2014 |
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ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
Cite this
The Oncogenic STP Axis Promotes Triple-Negative Breast Cancer via Degradation of the REST Tumor Suppressor. / Karlin, Kristen L.; Mondal, Gourish; Hartman, Jessica K.; Tyagi, Siddhartha; Kurley, Sarah J.; Bland, Chris S.; Hsu, Tiffany Y T; Renwick, Alexander; Fang, Justin E.; Migliaccio, Ilenia; Callaway, Celetta; Nair, Amritha; Dominguez-Vidana, Rocio; Nguyen, Don X.; Osborne, C. Kent; Schiff, Rachel; Yu-Lee, Li Yuan; Jung, Sung Y.; Edwards, Dean P.; Hilsenbeck, Susan G.; Rosen, Jeffrey M.; Zhang, Xiang H F; Shaw, Chad A.; Couch, Fergus J; Westbrook, Thomas F.
In: Cell Reports, Vol. 9, No. 4, 20.11.2014, p. 1318-1332.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The Oncogenic STP Axis Promotes Triple-Negative Breast Cancer via Degradation of the REST Tumor Suppressor
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.
UR - http://www.scopus.com/inward/record.url?scp=84912118947&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84912118947&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2014.10.011
DO - 10.1016/j.celrep.2014.10.011
M3 - Article
VL - 9
SP - 1318
EP - 1332
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 4
ER -