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

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. [Display omitted] •TNBCs commonly harbor posttranscriptional loss of the REST tumor suppressor protein•SCYL1, TEX14, and PLK1 constitute a new oncogenic signaling axis (STP axis)•The STP axis drives human TNBC transformation by reducing REST protein abundance•Inhibition of the STP axis impairs TNBC tumor progression and metastasis Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype for which the molecular drivers are poorly understood. Karlin et al. now demonstrate that SCYL1, TEX14, and PLK1 (“STP axis”) cooperatively trigger degradation of the REST tumor suppressor protein, a frequent event that may provide a therapeutic entry point for human TNBC.