Epidermal growth factor receptor (EGFR) has been detected in the nucleus in many tissues and cell lines. However, the potential functions of nuclear EGFR have largely been overlooked. Here we demonstrate that nuclear EGFR is strongly correlated with highly proliferating activities of tissues. When EGFR was fused to the GAL4 DNA-binding domain, we found that the carboxy terminus of EGFR contained a strong transactivation domain. Moreover, the receptor complex bound and activated AT-rich consensus-sequence-dependent transcription, including the consensus site in cyclin D1 promoter. By using chromatin immunoprecipitation assays, we further demonstrated that nuclear EGFR associated with promoter region of cyclin D1 in vivo. EGFR might therefore function as a transcription factor to activate genes required for highly proliferating activities.

␤-Catenin can function as an oncogene when it is translocated to the nucleus, binds to T cell factor or lymphoid enhancer factor family members, and transactivates its target genes. In this study, we demonstrate that cyclin D1 is one of the targets of ␤-catenin in breast cancer cells. Transactivation of ␤-catenin correlated significantly with cyclin D1 expression both in eight breast cell lines in vitro and in 123 patient samples. More importantly, we found that high ␤-catenin activity significantly correlated with poor prognosis of the patients and was a strong and independent prognostic factor in breast cancer. Our studies, therefore, indicated that ␤-catenin can be involved in breast cancer formation and͞or progression and may serve as a target for breast cancer therapy.

beta-catenin plays an important role in development and homeostasis. Deregulated beta-catenin is involved in oncogenesis. In this study, we found that beta-catenin can physically complex with NF-kappa B, resulting in a reduction of NF-kappa B DNA binding, transactivation activity, and target gene expression. Repressed NF-kappa B activity is found in human colon cancer cells in which beta-catenin is activated. Importantly, activated beta-catenin was found to inhibit the expression of NF-kappa B target genes, including Fas and TRAF1. Furthermore, a strong inverse correlation was identified between the expression levels of beta-catenin and Fas in colon and breast tumor tissues, suggesting that beta-catenin regulates NF-kappa B and its targets in vivo. Thus, beta-catenin may play an important role in oncogenesis through the crossregulation of NF-kappa B.

Hormone-refractory relapse is an inevitable and lethal event for advanced prostate cancer patients after hormone deprivation. A growing body of evidence indicates that hormone deprivation may promote this aggressive prostate cancer phenotype. Notably, androgen receptor (AR) not only mediates the effect of androgen on the tumor initiation but also plays the major role in the relapse transition. This provides a strong rationale for searching new effective agents targeting the down-regulation of AR to treat or prevent advanced prostate cancer progression. Here, we show that emodin, a natural compound, can directly target AR to suppress prostate cancer cell growth in vitro and prolong the survival of C3(1)/SV40 transgenic mice in vivo. Emodin treatment resulted in repressing androgen-dependent transactivation of AR by inhibiting AR nuclear translocation. Emodin decreased the association of AR and heat shock protein 90 and increased the association of AR and MDM2, which in turn induced AR degradation through proteasomemediated pathway in a ligand-independent manner. Our work indicates a new mechanism for the emodin-mediated anticancer effect and justifies further investigation of emodin as a therapeutic and preventive agent for prostate cancer. (Cancer Res 2005; 65(6): 2287-95)