Abstract 3291: Defining the role of the cellular polarity regulator Scrib in epithelial tumorigenesis
Authors: Pearson Helen B. , Godde Nathan , Elsum Imogen , Ryan Andrew , Tennstedt Pierre , Simon Ronald , Humbert Patrick O. 
Published: August 2012

In recent years, loss of cell polarity and tissue architecture has been defined as a hallmark of epithelial cancer yet the molecular mechanisms underlying this predisposition are not fully understood. Two distinct polarity programs are required for the correct assembly and function of all mammalian epithelial tissues; apical-basal polarity and non-canonical Wnt/planar cell polarity (1). The Scribble complex functions to establish and maintain both aspects of epithelial polarity and has been shown to mediate cell adhesion, migration and asymmetric cell division (2). In human colorectal, breast, and cervical cancers, expression of the Scribble complex member SCRIB is often mislocalised and deregulated, suggesting that polarity regulators plays a role in maintaining homeostasis of epithelial tissues (1,3). Scrib null mice are neonatal lethal owing to a neural tube closure defect. To determine the tumor suppressive role of Scrib within epithelial tissues, we have employed tissue specific Cre-LoxP technology to deplete Scrib specifically within the prostate, mammary or lung. Scrib depletion in these epithelial tissues results in tumor initiation, supporting previous work in Drosophila (1). We and others have previously shown that SCRIB loss stimulates Ras/MAPK signaling in vitro, suggesting that SCRIB negatively regulates the Ras/MAPK cascade to suppress tumorigenesis (4,5). We now show elevated p-ERK1/2 expression is a common feature of Scrib deficient tumors in vivo. Accordingly, administration of the MEK inhibitor PD0325901 in Scrib+/− mice partially rescued the hyperplastic prostate phenotype. Together, these studies establish that depletion of the polarity regulator Scrib can initiate murine tumorigenesis in several epithelial tissues in a process involving deregulation of the Ras/MAPK cascade. Interestingly, tissue specific activation of oncogenic K-ras in combination with Scrib depletion accelerated tumor progression in both the prostate and lung. Thus, K-ras activation and Scrib deficiency synergise to facilitate tumor growth, demonstrating that Scrib depletion can contribute to tumor progression in the presence of an additional oncogenic mutation. The clinical relevance of this research is highlighted by our observation that SCRIB deregulation strongly correlated with PSA recurrence free survival in human prostate cancer (3). Together, our findings suggest that the polarity network may hold prognostic value or provide a novel route for therapeutic intervention. (1) Humbert PO et al (2008) Oncogene 27(55):6888-6907 (2) Kallay LM et al (2006) J Cell Biochem 99: 647-64 (3) Pearson HB et al (2011) J Clin Invest 121(11):4257-4267 (4) Dow LE et al (2008) Oncogene 27(46):5988-6001 (5) Nagasaka K et al (2010) Oncogene 29(38):5311-5321

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3291. doi:1538-7445.AM2012-3291