Context dependent roles for p120-catenin in breast cancer progression

Abstract

Chapter 1 gives a general overview on epithelial homeostasis and the diverse functions p120 fulfills in adherens junction dynamics, RhoGTPase signaling and transcriptional regulation. Chapter 2 reviews the literature on the contribution of p120 in tumor development of different tissues with a focus on breast cancer. In chapter 3 we report on p120 loss in invasive breast cancer and its correlation to several clinicopathological characteristics. To further investigate the significance of p120 loss, we introduced a conditional p120 allele into a nonmetastatic mouse tumor model based on mammary-specific knockout of p53. Although p120 loss did not affect tumor onset, we observed a marked increase in metastatic dissemination. To determine the causal changes of p120 loss, we generated knockdown cell lines of mouse and human origin, and uncovered that p120 inactivation increased growth factor receptor (GFR) sensitivity, which translated into an increase in anoikis resistance - a hallmark of metastatic capacity. Furthermore, loss of p120 induced secretion of inflammatory cytokines, and as such facilitated formation of a prometastatic microenvironment. Chapter 4 reports on the role for cytosolic p120 in ILC tumor growth and metastasis. Here, p120 confers anoikis resistance through binding of Mrip, a known Rho-Rock antagonist, and subsequent activation of Rock signaling. In this setting, active Rock signaling controls anchorage-independent tumor growth and metastasis. Finally, the potential therapeutic ramifications of Rock inhibition in the treatment of ILC are discussed in chapter 5. Using inducible knock-down systems and pharmacological inhibition in a preclinical setting, we started to investigate the applicability of Rock inhibition for preclinical intervention of metastatic ILC.