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
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.
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
Cell Rep. 2014 Nov 20;9(4):1318-32. doi: 10.1016/j.celrep.2014.10.011. Epub 2014 Nov 6.
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.
对驱动乳腺癌的分子网络进行定义已带来了治疗干预措施并改善了患者生存率。然而，侵袭性三阴性乳腺癌亚型（TNBC）对靶向治疗仍然具有抗性，因为其分子病因尚未明确界定。在本研究中，我们采用正向遗传学筛选来发现驱动人类TNBC的致癌网络。SCYL1、TEX14和PLK1（“STP轴”）协同触发REST肿瘤抑制蛋白的降解，这在人类TNBC中是常见事件。STP轴通过磷酸化保守的REST磷酸化降解基序并介导REST与泛素连接酶βTRCP的相互作用来诱导REST降解。抑制STP轴会导致REST蛋白水平升高，并损害TNBC的转化、肿瘤进展和转移。STP轴的表达与人类TNBC中REST蛋白低水平以及TNBC患者的不良临床结局相关。我们的研究结果表明，STP-REST轴是人类TNBC的分子驱动因素。
