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

Abstract

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 Mü llerian 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.

ZEB1 overexpression associated with E-cadherin and microRNA-200 downregulation is characteristic of undifferentiated endometrial carcinoma

“…26 A larger study (88 endometrial carcinomas) from the same group included a expanded number of endometrioid endometrial carcinomas (71 grade 1/2 and 17 grade 3), but also 3 undifferentiated endometrial carcinomas and 12 endometrial carcinomas with a serous component. ZEB1 expression was only observed in three grade 3 endometrioid endometrial carcinomas, 27 although it was not specified whether the ZEB1-positive grade 3 endometrioid tumors were the same in the two studies. Differences between their series and the series presented herein might be due to different criteria to diagnose undifferentiated endometrial carcinomas.…”

Zeb1 is required for TrkB-induced epithelial-mesenchymal transition, anoikis resistance and metastasis

“…showed that PI(3) kinase contributes to TrkB signaling as well (including anoikis resistance; Douma et al, 2004), in aggregate these data suggest a model in which TrkB activates multiple pathways, some of which critically depend on Zeb1 (Figure 7). Several reports have shown a correlation between Zeb1 expression and the aggressiveness of tumors, including those of endometrial (Spoelstra et al, 2006;Singh et al, 2008), colon (Pena et al, 2005;Aigner et al, 2007b), breast (Aigner et al, 2007a), lung (Dohadwala et al, 2006), gallbladder (Adachi et al, 2009), ovarian (Bendoraite et al, 2010) and prostate origin (Graham et al, 2008). In colon cancer, Zeb1 expression is linked to loss of the basement membrane, which correlates with increased metastasis (Spaderna et al, 2006).…”

Additional effects of engineered stem cells expressing a therapeutic gene and interferon-β in a xenograft mouse model of endometrial cancer

“…Ishikawa endometrial cancer cells were subcutaneously implanted into NOD/ SCID mice, and the animals were observed for 4 weeks. When the tumor volume reached 250 mm 3 , Dm-DiI-stained HB1.F3.CD and HB1.F3.CD.IFN-β cells were subcutaneously injected into the mice at two different times. Two days after stem cell inoculation, the animals that received the stem cells were treated with 500 mg/kg/day of 5-FC.…”

“…Endometrioids are present in up to 80% of endometrial cancer patients and represent the natural progression of atypical complex hyperplasia due to estrogen imbalance (2). Endometrial cancer is classified into two types, type I and type II, according to aggressiveness, prognosis and molecular characteristics (3). Type I endometrial cancer is thought to have slower growth, hormone sensitivity, low stage and an excellent prognosis (4).…”