Loss of p120ctn : its effect on cadherin levels, development, and tumor progression

Abstract

p120 binds and is thought to regulate the cell-cell adhesion molecule E-cadherin. Experiments in a p120-deficient carcinoma cell line suggest a critical role for p120 in stabilizing E-cadherin. p120 downregulation occurs in a wide range of cancers and frequently correlates with E-cadherin loss. Thus I hypothesized that p120 is necessary for maintaining normal cadherin levels and that p120 loss may be a causal event leading to E-cadherin loss in tumors. To test this hypothesis, I knocked down p120 in vitro using siRNA and conditionally knocked out p120 in vivo using MMTV-Cre. My in vitro data demonstrate that p120 is essential for control of E-cadherin stability at the membrane and suggest that without p120, E-cadherin undergoes endocytosis and is degraded. By knocking out p120 in vivo with MMTV-Cre, I had intended to assess the effects of p120 loss on mammary tumorigenesis. Surprisingly, MMTV-Cre-mediated deletion of p120 led to postnatal lethality. Fortunately, MMTV-Cre is also expressed in the salivary gland, which is an excellent model system to study the effects of p120 ablation on glandular morphogenesis and development. As in vitro, p120 loss caused significant downregulation of E-cadherin. Concomitant with p120 loss, I observed premature dilation of salivary ducts and sporadic lack of cell polarity. As p120-null salivary glands developed, ducts extend and branch abnormally and acini do not develop, and indicating that p120 is critical to epithelial morphogenesis. Although these animals did not live long enough to develop cancer, they developed lesions that bore hallmarks of neoplasias including hyperplasia, loss of polarity, loss of cell-cell adhesion, and nuclear crowding. Together, these data reveal an essential role for p120 in regulating E-cadherin function and glandular morphogenesis, and they strongly support my hypothesis that p120 is a tumor modifier and/or suppressor.