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The Transcription Factor ZEB1 Is Aberrantly Expressed in Aggressive Uterine Cancers

¹ Department of Medicine, Division of Endocrinology, and ² Department of Pathology, University of Colorado Health Sciences Center at Fitzsimons, Aurora, Colorado; ³ Laboratory of Biomolecular Network Developmental Biology, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan; ⁴ Periodontics, Endodontics, and Dental Hygiene, Center for Genetics and Molecular Medicine, University of Louisville, Louisville, Kentucky; and ⁵ The University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Jennifer K. Richer, Department of Medicine, Division of Endocrinology, University of Colorado Health Sciences Center at Fitzsimons, MS 8106, Aurora, CO 80045. Phone: 303-724-3939; Fax: 303-724-3920; E-mail: jennifer.richer{at}uchsc.edu.

The transcription factor ZEB1 (EF1 in mice) has been implicated in cellular processes during development and tumor progression including epithelial to mesenchymal transition. EF1 null mice die at birth, but heterozygotes expressing a LacZ reporter inserted into the EF1 gene live and reproduce. Using these mice, we observed ZEB1 promoter activity in the virgin myometrium, and stroma and myometrium of the pregnant uterus. ZEB1 protein is up-regulated in the myometrium and endometrial stroma after progesterone or estrogen treatment of ovariectomized mice. In the normal human uterus, ZEB1 protein is increased in the myometrium and stroma during the secretory stage of the menstrual cycle. ZEB1 is not expressed in the normal endometrial epithelium. In malignancies of the uterus, we find that ZEB1 (a) is overexpressed in malignant tumors derived from the myometrium (leiomyosarcomas), (b) is overexpressed in tumor-associated stroma of low-grade endometrioid adenocarcinomas, and (c) is aberrantly expressed in the tumor epithelial cells of aggressive endometrial cancers. Specifically, in grade 3 endometrioid adenocarcinomas and uterine papillary serous carcinomas, ZEB1 could be expressed in the epithelial-derived carcinoma cells as well as in the stroma. In malignant mixed Müllerian tumors, the sarcomatous component always expresses ZEB1, and the carcinomatous component can also be positive. In summary, ZEB1 is normally regulated by both estrogen and progesterone receptors, but in uterine cancers, it is likely no longer under control of steroid hormone receptors and becomes aberrantly expressed in epithelial-derived tumor cells, supporting a role for ZEB1 in epithelial to mesenchymal transitions associated with aggressive tumors. (Cancer Res 2006; 66(7): 3893-902)

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