ZEB1 expression in type I vs type II endometrial cancers:: a marker of aggressive disease

被引:117
作者
Singh, Meenakshi [1 ]
Spoelstra, Nicole S. [1 ]
Jean, Annie [1 ]
Howe, Erin [1 ]
Torkko, Kathleen C. [1 ]
Clark, Hilda R. [1 ]
Darling, Douglas S. [2 ]
Shroyer, Kenneth R. [1 ]
Horwitz, Kathryn B. [1 ,3 ]
Broaddus, Russell R. [4 ]
Richer, Jennifer K. [1 ]
机构
[1] Univ Colorado, Hlth Sci Ctr, Dept Pathol, Aurora, CO 80045 USA
[2] Univ Louisville, Ctr Genet & Mol Med, Dept Periodont Endodont & Dent Hyg, Louisville, KY 40292 USA
[3] Univ Colorado, Div Endocrinol, Dept Med, Aurora, CO 80045 USA
[4] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA
关键词
ZEB1; delta EF1; Zfhx1a; E-cadherin; type I and type II endometrial cancer; epithelial to mesenchymal transition;
D O I
10.1038/modpathol.2008.82
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
Zinc-finger E-box-binding homeobox 1 (ZEB1) is a transcription factor containing two clusters of Kruppel-type zinc-fingers, by which it binds E-box-like sequences on target DNAs. A role for ZEB1 in tumor progression, specifically, epithelial to mesenchymal transitions, has recently been revealed. ZEB1 acts as a master repressor of E-cadherin and other epithelial markers. We previously demonstrated that ZEB1 is confined to the stromal compartment in normal endometrium and low-grade endometrial cancers. Here, we quantify ZEB1 protein expression in endometrial samples from 88 patients and confirm that it is expressed at significantly higher levels in the tumor-associated stroma of low-grade endometrioid adenocarcinomas (type I endometrial cancers) compared to hyperplastic or normal endometrium. In addition, as we previously reported, ZEB1 is aberrantly expressed in the epithelial-derived tumor cells of highly aggressive endometrial cancers, such as FIGO grade 3 endometrioid adenocarcinomas, uterine serous carcinomas, and malignant mixed Mullerian tumors (classified as type II endometrial cancers). We now demonstrate, in both human endometrial cancer specimens and cell lines, that when ZEB1 is inappropriately expressed in epithelial-derived tumor cells, E-cadherin expression is repressed, and that this inverse relationship correlates with increased migratory and invasive potential. Forced expression of ZEB1 in the nonmigratory, low-grade, relatively differentiated Ishikawa cell line renders them migratory. Conversely, reduction of ZEB1 in a highly migratory and aggressive type II cell line, Hec50co, results in reduced migratory capacity. Thus, ZEB1 may be a biomarker of aggressive endometrial cancers at high risk of recurrence. It may help identify women who would most benefit from chemotherapy. Furthermore, if expression of ZEB1 in type II endometrial cancers could be reversed, it might be exploited as therapy for these highly aggressive tumors.
引用
收藏
页码:912 / 923
页数:12
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