This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Spoelstra, N. S. Articles by Richer, J. K. Search for Related Content PubMed PubMed Citation Articles by Spoelstra, N. S. Articles by Richer, J. K.

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)

This article has been cited by other articles:

				A. E. Sayan, T. R. Griffiths, R. Pal, G. J. Browne, A. Ruddick, T. Yagci, R. Edwards, N. J. Mayer, H. Qazi, S. Goyal, et al. SIP1 protein protects cells from DNA damage-induced apoptosis and has independent prognostic value in bladder cancer PNAS, September 1, 2009; 106(35): 14884 - 14889. [Abstract] [Full Text] [PDF]

				D. R. Cochrane, N. S. Spoelstra, E. N. Howe, S. K. Nordeen, and J. K. Richer MicroRNA-200c mitigates invasiveness and restores sensitivity to microtubule-targeting chemotherapeutic agents Mol. Cancer Ther., May 1, 2009; 8(5): 1055 - 1066. [Abstract] [Full Text] [PDF]

				C. P. Bracken, P. A. Gregory, N. Kolesnikoff, A. G. Bert, J. Wang, M. F. Shannon, and G. J. Goodall A Double-Negative Feedback Loop between ZEB1-SIP1 and the microRNA-200 Family Regulates Epithelial-Mesenchymal Transition Cancer Res., October 1, 2008; 68(19): 7846 - 7854. [Abstract] [Full Text] [PDF]

				M. Korpal, E. S. Lee, G. Hu, and Y. Kang The miR-200 Family Inhibits Epithelial-Mesenchymal Transition and Cancer Cell Migration by Direct Targeting of E-cadherin Transcriptional Repressors ZEB1 and ZEB2 J. Biol. Chem., May 30, 2008; 283(22): 14910 - 14914. [Abstract] [Full Text] [PDF]

				T. R. Graham, H. E. Zhau, V. A. Odero-Marah, A. O. Osunkoya, K. S. Kimbro, M. Tighiouart, T. Liu, J. W. Simons, and R. M. O'Regan Insulin-like Growth Factor-I-Dependent Up-regulation of ZEB1 Drives Epithelial-to-Mesenchymal Transition in Human Prostate Cancer Cells Cancer Res., April 1, 2008; 68(7): 2479 - 2488. [Abstract] [Full Text] [PDF]

				S.-M. Park, A. B. Gaur, E. Lengyel, and M. E. Peter The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2 Genes & Dev., April 1, 2008; 22(7): 894 - 907. [Abstract] [Full Text] [PDF]

				Y. Liu, S. El-Naggar, D. S. Darling, Y. Higashi, and D. C. Dean Zeb1 links epithelial-mesenchymal transition and cellular senescence Development, February 1, 2008; 135(3): 579 - 588. [Abstract] [Full Text] [PDF]

				M. Kuppuswamy, S. Vijayalingam, L.-J. Zhao, Y. Zhou, T. Subramanian, J. Ryerse, and G. Chinnadurai Role of the PLDLS-Binding Cleft Region of CtBP1 in Recruitment of Core and Auxiliary Components of the Corepressor Complex Mol. Cell. Biol., January 1, 2008; 28(1): 269 - 281. [Abstract] [Full Text] [PDF]

				J. Mejlvang, M. Kriajevska, C. Vandewalle, T. Chernova, A. E. Sayan, G. Berx, J. K. Mellon, and E. Tulchinsky Direct Repression of Cyclin D1 by SIP1 Attenuates Cell Cycle Progression in Cells Undergoing an Epithelial Mesenchymal Transition Mol. Biol. Cell, November 1, 2007; 18(11): 4615 - 4624. [Abstract] [Full Text] [PDF]