THE ESTROGEN-DEPENDENT C-JUNER PROTEIN CAUSES A REVERSIBLE LOSS OF MAMMARY EPITHELIAL-CELL POLARITY INVOLVING A DESTABILIZATION OF ADHERENSJUNCTIONS

Members of the epidermal growth factor (EGF) receptor family are known to be specifically involved in mammary carcinogenesis. As a nuclear t arget of activated receptors, we examined c-Jun in mammary epithelial cells. For this. we used a c-JunER fusion protein which was tightly co ntrolled by estrogen. Activation of the JunER by hormone resulted in t he transcriptional regulation of a variety of AP-1 target genes. Hormo ne-activated JunER induced the loss of epithelial polarity, a disrupti on of intercellular junctions and normal barrier function and the form ation of irregular multilayers. These changes were completely reversib le upon hormone withdrawal. Loss of epithelial polarity involved redis tribution of both apical and basolateral proteins to the entire plasma membrane. The redistribution of E-cadherin and beta-catenin was accom panied by a destabilization of complexes formed between these two prot eins, leading to an enrichment of beta-catenin in the detergent-solubl e fraction. Uninduced cells were able to form three-dimensional tubula r structures in collagen I gels which were disrupted upon JunER activa tion, leading to irregular cell aggregates. The JunER-induced disrupti on of tubular structures was dependent on active signaling by growth f actors. Moreover, the effects of JunER could be mimicked in normal cel ls by the addition of acidic fibroblast growth factor (aFGF). These da ta suggest that a possible function of c-Jun in epithelial cells is to modulate epithelial polarity and regulate tissue organization, proces ses which may be equally important for both normal breast development and as initiating steps in carcinogenesis.