The zinc finger E-box binding transcription factor ZEB1 (deltaEF1/Nil-2-a/AREB6/zfhx1a/TCF8/zfhep/BZP) is emerging as an important regulator of the epithelial to mesenchymal transitions (EMT) required for development and cancer metastasis. ZEB1 promotes EMT by repressing genes contributing to the epithelial phenotype while activating those associated with the mesenchymal phenotype. TCF8 (zfhx1a), the gene encoding ZEB1, is induced by several potentially oncogenic ligands including TGF-beta, estrogen, and progesterone. TGF-beta appears to activate EMT, at least in part, by inducing ZEB1. However, our understanding of how ZEB1 contributes to signaling pathways elicited by estrogen and progesterone is quite limited, as is our understanding of its functional roles in normal adult tissues. To begin to address these questions, a human tissue mRNA array analysis was done. In adults, the highest ZEB1 mRNA expression is in bladder and uterus, whereas in the fetus highest expression is in lung, thymus, and heart. To further investigate the regulation of TCF8 by estrogen, ZEB1 mRNA was measured in ten estrogen-responsive cell lines, but it is only induced in the OV266 ovarian carcinoma line. Although high expression of ZEB1 mRNA is estrogen-dependent in normal human ovarian and endometrial biopsies, high expression is estrogen-independent in late stage ovarian and endometrial carcinomas, raising the possibility that deregulated expression promotes cancer progression. In contrast, TCF8 is at least partially deleted in 4 of 5 well-differentiated, grade I endometrial carcinomas, which may contribute to their non-aggressive phenotype. These data support the contention that high ZEB1 encourages gynecologic carcinoma progression.

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The zinc finger E-box binding protein 1 (ZEB1) transcription factor belongs to a two-member family of zinc-finger homeodomain proteins involved in physiological and pathological events mostly relating to cell migration and epithelial to mesenchymal transitions (EMTs). ZEB1 (also known as δEF1, zfhx1a, TCF8, and Zfhep) plays a key role in regulating such diverse processes as T-cell development, skeletal patterning, reproduction, and cancer cell metastasis. However, the factors that regulate its expression and consequently the signaling pathways in which ZEB1 participates are poorly defined. Because it is induced by estrogen and progesterone and is high in prostate cancer, we investigated whether tcf8, which encodes ZEB1, is regulated by androgen. Data herein demonstrate that tcf8 is induced by dihydrotestosterone (DHT) in the human PC-3/AR prostate cancer cell line and that this induction is mediated by two androgen response elements (AREs). These results demonstrate that ZEB1 is an intermediary in androgen signaling pathways.

Two-thirds of patients who present with metastatic prostate cancer (PC) are dead within 5 years of diagnosis. The comparable survival rate for patients with localized disease is 100%, which clearly stresses the need for pursuing and developing bioassays that allow prediction of which localized cases are most likely to metastasize. The commonly assayed prostate specific antigen (PSA), while touted as a transformation biomarker, has recently proven to be problematic in the area of false positive diagnoses. It remains, however, a hallmark gene for studying androgen regulation as its expression is reliably stimulated by androgens such as dihydrotestosterone (DHT). Herein, we have elucidated the effects of flutamide (a defined anti-androgen) and DHT on the expression of PSA and Zinc finger E-box Binding factor (ZEB-1). Additionally, we assayed the androgenic capabilities of two DHT derivatives on expression of PSA. Our previous research had identified ZEB-1 as a putative biomarker for the onset of metastasis in prostate cancer. The expression of this gene is regulated by androgen and decreases sharply at metastasis. In the current study, the effects of 1 and 10 nM flutamide, in combination with 1 and 10 nM DHT, on expression of ZEB-1 and PSA, were investigated in 22Rv1, an androgen-responsive human PC cell line. Also in this cell line, the effects of testosterone propionate and dehydroisoandrosterone were studied. Our research confirmed the feasibility of considering ZEB-1 a metastatic PCa biomarker, using the highly sensitive technique of real-time polymerase chain reaction (RT-PCR). Interestingly, it also revealed the danger of using flutamide as a therapeutic antagonist, as we demonstrate herein its alarming capability to behave as an agonist.