Regulation by Zeb1 and Src Family Kinases

Expression of E-cadherin is used to monitor the epithe-lial phenotype, and its loss is suggestive of epithelial-mesenchymal transition (EMT). EMT triggers tumor me-tastasis. Exit from EMT is marked by increasedE-cadherin expression and is considered necessary fortumor growth at sites of metastasis; however, the mech-anisms associated with exit from EMT are poorly under-stood. Herein are analyzed 185 prostate cancer metas-tases, with significantly higher E-cadherin expressionin bone than in lymph node and soft tissue metastases.To determine the molecular mechanisms of regulationofE-cadherinexpression,threestableisogeniccelllinesfromDU145werederivedthatdifferinstructure,migra-tion, and colony formation on soft agar and Matrigel.When injected into mouse tibia, the epithelial sublinegrows most aggressively, whereas the mesenchymalsubline does not grow. In cultured cells, ZEB1 and Srcfamily kinases decrease E-cadherin expression. In con-trast, in tibial xenografts, E-cadherin RNA levels in-crease eight- to 10-fold despite persistent ZEB1 expres-sion, and in all ZEB1-positive metastases (10 of 120),ZEB1andE-cadherinproteinswereco-expressed.Thesedata suggest that transcriptional regulation of E-cad-herin differs in cultured cells versus xenografts, whichmore faithfully reflect E-cadherin regulation in cancersin human beings. Furthermore, the aggressive nature ofxenografts positive for E-cadherin and the frequency ofmetastases positive for E-cadherin suggest that high E-cadherin expression in metastatic prostate cancer is as-sociated with aggressive tumor growth.