Tumor progression in mouse mammary carcinoma is associated with expression of VE-cadherin and HIF hydroxylases

M. Rezaei, ¹M. Labelle, A. Kettelhake, A. Kuzmanov, G. Baretton and G. Breier

Department of Pathology, University of Technology, Dresden, Germany, ¹MIT Center for Cancer Research, Cambridge, USA

Aims:  Epithelial mesenchymal transition (EMT) is an important event during carcinoma progression, which contributes to increased invasive and metastatic potential of cancer cells. One of the hallmarks of this transition is the switch in cadherin expression. In this study, the modulation of cadherin expression during EMT was analyzed in an experimental model of breast tumor progression. The second part of the project was dedicated to analyse the level of hypoxia-inducible factor (HIF) hydroxylases in the tumor cells which are representing different stages of tumor progression.

Methods: Transfections; proliferation assays; tumor experiments immunofluorescence; immunohistochemistry; RNA interference; RT-PCR and western blot.

Results: We show that vascular endothelial (VE)-cadherin is induced during EMT in mouse mammary tumor cells and is aberrantly expressed in invasive human breast carcinomas. VE-cadherin expression enhanced the capacity of fibroblastoid tumor cells to proliferate. Analysis of the signaling mechanisms involved revealed that VE-cadherin expression enhances the transforming growth factor (TGF)-beta signaling pathway which also contributes to malignant tumor cell proliferation. Furthermore we detected that hypoxia-inducible factor (HIF) hydroxylases are differentially expressed in tumor cell lines which are representing different stages of tumor progression.

Conclusions: Our findings provide evidence for a novel function of VE-cadherin in tumor progression and reveal a previously unknown molecular link between VE-cadherin expression and TGF-beta signalling. Moreover they suggest that HIF hydroxylases play a role in EMT and breast cancer progression.