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Vascular Endothelial Cadherin Promotes Breast Cancer Progression via Transforming Growth Factor β Signaling

¹ Institute of Pathology, ² Institute of Physiology, Medical Faculty, University of Dresden, Dresden, Germany and ³ Max Planck Institute of Molecular Biomedicine, Muenster, Germany

Requests for reprints: Georg Breier, Institute of Pathology, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Fetscherstr 74, 01307 Dresden, Germany. Phone: 49-0-351-458-5278; E-mail: georg.breier{at}uniklinikum-dresden.de.

Key Words: VE-cadherin • epithelial-to-mesenchymal transition • mammary carcinoma

Epithelial-to-mesenchymal transition (EMT) is an important event during carcinoma progression and leads to increased tumor cell malignancy. Here, we show that vascular endothelial (VE)-cadherin is induced during EMT in mammary tumor cells and is aberrantly expressed in invasive human breast carcinomas. VE-cadherin enhanced the capacity of fibroblastoid tumor cells to proliferate, form cord-like invasive structures, and adhere to endothelial cells, characteristics that are key contributors to their increased malignancy and metastatic potential. Consistently, VE-cadherin expression in malignant fibroblastoid tumor cells promoted the growth of experimental mammary carcinomas in vivo. Analysis of the signaling mechanisms involved revealed that VE-cadherin expression influences the levels of Smad2 phosphorylation and expression of target genes of transforming growth factor-β (TGF-β), a major mediator of advanced tumor progression and malignant tumor cell proliferation. VE-cadherin might thus promote tumor progression not only by contributing to tumor angiogenesis but also by enhancing tumor cell proliferation via the TGF-β signaling pathway. This article provides evidence for a novel function of VE-cadherin in tumor progression and reveals a previously unknown molecular link between VE-cadherin expression and TGF-β signaling. Our findings may have important implications for the clinical application of anti–VE-cadherin strategies. [Cancer Res 2008;68(5):1388–97]