Abstract A059: Context-dependent regulation of breast cancer metastasis by E-cadherin and p120-catenin

Abstract

Abstract While it is well established that mutational inactivation of E-cadherin is a causal event in the development and progression of invasive breast cancer, still little is known about how this event controls the metastatic process. Using conditional E-cadherin knockout mouse models of human invasive lobular carcinoma (ILC), we recently demonstrated that p120-catenin (p120) translocates to the cytosol upon E-cadherin inactivation. Here, it acts as an oncogene by regulating Rock-dependent control of tumor growth and metastasis through binding and inhibition of the Rho antagonist Mrip. Furthermore, new evidence indicates that p120 shuttles to the nucleus where it relieves Kaiso-dependent transcriptional repression of Wnt11, leading to autocrine activation of RhoA. Conversely, since p120 controls E-cadherin stability and turnover, we also addressed the hypothesis that p120 may function as a tumor suppressor in breast cancer. In contrast to E-cadherin loss and the development of metastatic ILC, we show that somatic inactivation of p120 results in the formation of stromal-dense tumors resembling human metaplastic carcinoma that metastasize to lungs and lymph nodes. Mechanistically, we demonstrate that acquisition of metastatic potential was acquired through relieve of E-cadherin-dependent repression of growth factor receptor (GFR) function, leading to hyper-activation of GFR signaling and subsequent anchorage independence. In summary, our data show that p120 can act as an oncogene or metastasis suppressor, depending on context and timing of junctional inactivation. Furthermore, our experiments indicate that targeted intervention strategies using Rock inhibitors may be applicable for the treatment of ILC. Based on our findings we also anticipate that patients suffering from E-cadherin or p120 negative breast cancer will benefit from clinically established inhibitors targeting GFR/PI3K/AKT/FOXO pathways in the absence of GFR or PIK3CA activating mutations. Citation Format: Ron CJ Schackmann, Sjoerd Klarenbeek, Miranda van Amersfoort, Jos Jonkers, Paul van Diest, Patrick Derksen. Context-dependent regulation of breast cancer metastasis by E-cadherin and p120-catenin. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A059.