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The Transcriptional Repressor ZEB1 Promotes Metastasis and Loss of Cell Polarity in Cancer

¹ Department of Visceral Surgery, University of Freiburg, Freiburg, Germany; ² Department of Pathology and ³ Nikolaus-Fiebiger-Center, University of Erlangen, Erlangen, Germany; ⁴ Max F. Perutz Laboratories, Medical University Vienna, Vienna, Austria; ⁵ Department of Pathology, University of Munchen, Munich, Germany; and ⁶ First Department of Internal Medicine, University of Mainz, Mainz, Germany

Requests for reprints: Thomas Brabletz, Department of Visceral Surgery, University of Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany. Phone: 49-0761270-2577; Fax: 49-0761270-2779; E-mail: thomas.brabletz{at}uniklinik-freiburg.de.

Invasion and metastasis are the hallmarks of malignant tumor progression and the main cause of death in cancer. The embryonic program "epithelial-mesenchymal transition" (EMT) is thought to trigger invasion by allowing tumor cell dissemination. Here, we describe that the EMT-inducing transcriptional repressor ZEB1 promotes colorectal cancer cell metastasis and loss of cell polarity. Thereby, ZEB1 suppresses the expression of cell polarity factors, in particular of Lgl2, which we found reduced in colorectal and breast cancers. We further show that retention of Lgl2 expression is critical for the epithelial phenotype and that its loss might be involved in metastasis. Thus, by linking EMT, loss of polarity, and metastasis, ZEB1 is a crucial promoter of malignant tumor progression. [Cancer Res 2008;68(2):537–44]

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