Hormonal Regulation of ZEB-1 and Implication for Progression of Human Reproductive Cancers.

The human Zinc finger E-box Binding (ZEB)-1 protein belongs to a family of transcription factors involved in critical developmental processes. Yet little is known of the mechanisms by which ZEB-1 is regulated. Our lab has recently demonstrated that the expression of ZEB-1 is induced by estrogen (E) in the ovarian cancer cell line Ov266 and that it is regulated by dihydrotestosterone (DHT) in the human PC-3/AR prostate carcinoma cell line. Interestingly, a dose-response assay indicates the expression of ZEB-1 is induced by 5 nM DHT and repressed at higher dosages. Cloning and analysis of approximately 1000 bp upstream of the translation start site of hZEB-1 revealed a number of putative E and androgen (A) response elements. Transient transfection assays indicate that this region is sufficient to confer responsiveness to both steroids. To determine whether expression of ZEB-1 could serve as a marker of tumor progression, real-time PCR (rtPCR) assays were performed on staged human reproductive carcinomas. Preliminary results indicate that expression of ZEB-1 increases as the normal ovary transforms to a primary carcinoma and continues to increase as the cancer progresses to an invasive and finally a metastatic state. There is an approximate 12-fold elevation in the expression of ZEB-1 in metastatic ovarian carcinoma relative to its expression in in situ cancers. rtPCR is currently being utilized to investigate the potential changes in ZEB-1 expression in breast and prostate cancer during the progression of these diseases. These data raise the possibility that overexpression of ZEB-1 contributes to the progression of reproductive carcinomas. [ABSTRACT FROM AUTHOR]