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.
Highlights
Breast cancer is a heterogeneous disease comprised of three clinical subtypes: estrogen receptor positive (ER+), HER2 positive (HER2+), and triple negative breast cancer (TNBC)
Using an unbiased genetic screen, we identified SCYL1, TEX14 and Polo-like kinase 1 (PLK1) as components of an oncogenic signaling axis that prominently regulates RE-1 silencing transcription factor (REST) abundance and stability
To determine whether REST is compromised by alternative mechanisms in human breast cancer, we evaluated REST protein levels in primary human breast tumors (n=185) (Fig. 1A and Fig S1A)
Summary
Breast cancer is a heterogeneous disease comprised of three clinical subtypes: estrogen receptor positive (ER+), HER2 positive (HER2+), and triple negative breast cancer (TNBC). The identification of prominent molecular drivers of breast cancers (ER and HER2) has enabled the development of targeted therapies that have improved survival rates for patients with ER+ and HER2+ breast cancers (Arteaga et al, 2012; Osborne, 1998; Slamon et al, 1989). REST functions as a tumor suppressor in epithelial cancers (Westbrook et al, 2005), the mechanisms by which REST restrains tumorigenesis remains undefined. REST is frequently inactivated in epithelial malignancies such as colon and lung cancer via gene deletion, inactivating mutations (Westbrook et al, 2005), epigenetic silencing (Kreisler et al, 2010), and rarely through alternative splicing (Coulson et al, 2000; Wagoner et al, 2010). While REST potently suppresses transformation of cells derived from mammary epithelium (Westbrook et al, 2005), it has remained unclear whether REST is inactivated in breast cancer and what the molecular mechanisms of such misregulation might be
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