Epigallocatechin-3-gallate (EGCG) down-regulates the androgen receptor and the IGF pathway in the prostate of TRAMP mice

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Prostate cancer (PCa), a major health concern for men, starts to develop early in life. By their sixties, over 40% of men have high-grade PIN, the precursor to PCa. Many have implemented chemopreventive agents into their daily diet in an attempt to delay the onset of a variety of cancers. Green tea, one such agent, has been shown to be chemopreventive in breast, skin, and prostate cancers. We hypothesized that EGCG, the major polyphenol found in green tea, will exert its chemopreventive effect in the prostate via regulation of sex steroid and growth factor signaling pathways. In the current study, TRAMP (Transgenic Adenocarcinoma Mouse Prostate) heterozygous male offspring were routinely produced as [TRAMP C57BL/6 females X C57BL/6 male breeders]. Five week old male TRAMP offspring were fed phytoestrogen-free powdered AIN-76A diet and 0.06% EGCG in tap water. The latter is based on a green tea extract dose that previously showed chemoprevention in this model. Animals were sacrificed at 12 weeks of age and ventral and dorsolateral prostates were removed for immunoblot analyses or ELISA to evaluate sex steroid and growth factor signaling. In the ventral prostate lobe, EGCG significantly decreased androgen receptor (AR), insulin-like growth factor-1 (IGF-1), insulin-like growth factor receptor 1 (IGF-R1), and phospho-extracellular regulating kinase 1 and 2 (P-ERK 1/2). In contrast, in the dorsolateral lobe, EGCG significantly decreased IGF-1, but did not alter AR, IGF-R1, or P-ERK 1/2. Elevated IGF-1 is associated with a higher risk for prostate, breast, lung, and colorectal cancer and P-ERK 1/2 activation leads to the transcription of genes responsible for cell growth and proliferation. EGCG mediates most of its action via the VP, although IGF-1 was decreased in both lobes. In summary, the attenuation of the androgen receptor, decrease in the potent growth factor IGF-1 and its receptor, IGF-R1, and the downregulation of downstream effectors, P-ERK1/2 in the VP, may provide a biochemical basis for EGCG suppressing PCa without significant toxicity.