Role of estrogen receptor beta in prostate disease

Despite the androgen dependence of the prostate, estrogens are also known to play a role in both the normal and diseased prostate. Unlike the adverse effects caused by estrogens through the estrogen receptor alpha (ERα), ERβis proposed to have beneficial effects in the prostate. Previous studies have shown that activating ERβ using a selective estrogen receptor modulator (8β-VE2) abrogates hyperplasia in aromatase knockout mice. Chapter three examines the mechanisms by which this abrogation is achieved, and shows unequivocally the ability of 8β-VE2 to abrogate hyperplasia in mouse models of hyperplasia. Furthermore, using human patient xenografts of benign prostatic hyperplasia (BPH) these results are extended to human tissues, showing decreased proliferation and increased apoptosis in all cell types of the prostate, including the basal cells. Castrate-resistance is a significant issue in prostate cancer, as there is currently no cure for this stage of the disease. Given that our studies in normal and benign tissues showed targeting of castrate-resistant, regenerative basal cells, we evaluated the efficacy of 8β-VE2 on cancer cells and tissues. Chapter three of this thesis examines the ability of short-term treatments of 8β-VE2 to target castrate-resistant cell lines and human xenografts of localized (i.e. hormone-responsive) cancers. Here, it was observed that the drug could indeed target cells in both these models, by directly activating ERβ, and utilizing the extrinsic pathway of apoptosis via TNFα. Chapter four demonstrates the impact of 8βVE2 on the regenerative stem/progenitor fraction of the prostate. Specifically, we show that unlike castration, the targeting of p63+ murine prostatic cells (which have proven regenerative capacity) by 8β-VE2 results in the inability of the prostate to regenerate, as indicated by the presence of cystic atrophy in glands of the prostate and altered secretory activity. Furthermore this chapter shows that the drug targets stem-enriched populations of murine and human prostatic cells. Significantly, a population of castrate-resistant human stem-enriched cells (shown by other authors to contain the cells-of-origin for prostate cancer) undergoes apoptosis when treated with 8β-VE2. Finally, chapter five evaluates the effects of other selective estrogen receptor modulators on the prostate; briefly, a non-steroidal, plant-derived ERβ agonist; S-equol were shown to have similar effects to 8β-VE2, inducing apoptosis in castrate-resistant basal cells and suppressing proliferation in mouse models. Evaluation of androgen receptor in these tissues indicated that down-regulation of AR could be one mechanism by which this class of agonist has biological outcomes. Overall this thesis demonstrates three key points: 8β-VE2 abrogates prostatic hyperplasia by the reduction of proliferation and induction of apoptosis, is able to do so in both benign and malignant human tissues and that activation of ERβ results in permanent reduction in regenerative capacity via the targeting of stem-enriched and regenerative populations. Collectively, these data highlight the importance of revisiting estrogens as therapies for prostate cancer in both its localized and castrate-resistant forms, and for the treatment of benign prostatic hyperplasia.