Targeting estrogen- and hedgehog-signaling pathways in prostate cancer
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Prostate cancer is the second most frequent cause of cancer deaths in men, and the risk to develop cancer increases with age. Since the lifespan of the society is progressively increasing, the importance of preventing the development of this common disease is becoming more urgent. The prevention and therapy options for non-metastatic prostate cancer are available but limited. For the androgen-insensitive, metastatic form of prostate cancer there still is no effective therapy. Our laboratory has an estrogen receptor based perspective on prostate cancer. We are using a transgenic mouse as an animal model to study the development and treatment of prostate cancer. We are also investigating a selection of botanical compounds that have been implicated as cancer protective either by traditional medicine or in modern cancer research. The TRAMP (TRansgenic Adenocarcinoma of the Mouse Prostate) model enables us to study the specific roles of estrogen receptors in prostate cancer progression. The expression of the two estrogen receptors alpha (ERα) and beta (ERβ) in TRAMP mouse prostates switches upon progression from non-metastatic to metastatic tumor phenotype. During earlier stages of cancer, ERβ is the main estrogen receptor present, as the phenotype of the cancer changes to the more neuro-endocrine like, the expression of ERβ decreases and ERα seems to remain the only active receptor. Initial studies in the Lubahn lab and elsewhere led us to hypothesize a protective role for ERβ in prostate cancer tumorigenesis. The presence of ERβ only seems to prevent or slow down the incidence of (PDC) poorly differentiated carcinoma in contrast to ERα, which promotes the metastatic, neuro-endocrine like phenotype. We have found though a study in double transgenic mice, that were WT and KO for estrogen receptors alpha or beta on a TRAMP background, that ERαKO mice did not develop poorly differentiated carcinoma (75% reduction compared to control animals), however ERβKO mice had significantly increased PDC incidence and had double the PDC compared to animals WT for both receptors. We were also interested in cancer protective properties of a variety of botanical compounds, reported in the literature to be potentially beneficial for prostate health, and widely bought through health food stores around the country. We specifically investigated apigenin, baicalein, curcumin, EGCG, genistein, quercetin, and resveratrol, both in vitro and in vivo. All seven compounds were able to delay prostate cancer cell growth of both human (LNCaP, PC3, and PC3M) and mouse (TRAMP-C2) prostate cancer cell lines. All seven compounds combinations were also able to inhibit or delay prostate cancer incidence by up to 80%, specifically at the well differentiated carcinoma stage, when fed to TRAMP mice. The protective effects were only present in ERWT mice, indicating a need for both receptors for these compounds to act on the prostate cancer incidence. I introduced a new pathway to the lab, the hedgehog signaling pathway, which has been recently found to play a role in prostate cancer, specifically in metastatic cancer. Several botanicals used in the lab were able to inhibit the hedgehog pathway as indicated by decreasing Gli1 levels. With IC[subscript 50] values ranging from <1μM to 25μM these compounds demonstrated hedgehog pathway inhibition by deceasing Gli1 mRNA concentration by up to 95% and down regulating Gli-reporter activity by 80%. Also, both estrogen and ICI inhibit Gli1 mRNA in TRAMP-C2 cells, and Gli-reporter activity in Shh Light II cells. My research sheds light on an additional mechanism by which phytoestrogens are potentially protecting against cancer. My work suggests a potential new treatment target for addressing both slow and fast growing prostate cancers. Based on data presented here, we propose that a combination of ERα antagonists, ERβ agonists and selected botanicals should present a comprehensive prostate cancer remedy.