Prostate & Breast Cancer Research Program, Department of Anatomy & Developmental Biology, Monash University, Clayton, Victoria, Australia.
PLoS One. 2012;7(7):e40732. doi: 10.1371/journal.pone.0040732. Epub 2012 Jul 10.
Androgen depletion is the primary treatment for prostate disease; however, it fails to target residual castrate-resistant cells that are regenerative and cells of origin of prostate cancer. Estrogens, like androgens, regulate survival in prostatic cells, and the goal of this study was to determine the advantages of selective activation of estrogen receptor β (ERβ) to induce cell death in stem cells that are castrate-resistant. Here we show two cycles of short-term ERβ agonist (8β-VE2) administration this treatment impairs regeneration, causing cystic atrophy that correlates with sustained depletion of p63+ basal cells. Furthermore, agonist treatment attenuates clonogenicity and self-renewal of murine prostatic stem/progenitor cells and depletes both murine (Lin(-)Sca1(+)CD49f(hi)) and human (CD49f(hi)Trop2(hi)) prostatic basal cells. Finally, we demonstrate the combined added benefits of selective stimulation of ERβ, including the induction of cell death in quiescent post-castration tissues. Subsequent to castration ERβ-induces further apoptosis in basal, luminal and intermediate cells. Our results reveal a novel benefit of ERβ activation for prostate disease and suggest that combining selective activation of ERβ with androgen-deprivation may be a feasible strategy to target stem cells implicated in the origin of prostatic disease.
雄激素剥夺是前列腺疾病的主要治疗方法；然而，它不能针对再生的和前列腺癌起源的残余去势抵抗细胞。雌激素与雄激素一样，调节前列腺细胞的存活，本研究的目的是确定选择性激活雌激素受体β（ERβ）以诱导去势抵抗干细胞死亡的优势。在这里，我们展示了两次短期 ERβ激动剂（8β-VE2）给药，这种治疗会损害再生，导致囊泡萎缩，与持续耗尽 p63+基底细胞相关。此外，激动剂治疗可减弱小鼠前列腺干细胞/祖细胞的克隆形成能力和自我更新能力，并耗尽小鼠（Lin(-)Sca1(+)CD49f(hi)）和人（CD49f(hi)Trop2(hi)）前列腺基底细胞。最后，我们证明了选择性刺激 ERβ的联合附加益处，包括诱导静止去势后组织中的细胞死亡。去势后 ERβ诱导基底细胞、腔细胞和中间细胞进一步凋亡。我们的研究结果揭示了 ERβ激活在前列腺疾病中的新优势，并表明选择性激活 ERβ与雄激素剥夺相结合可能是一种可行的策略，可靶向参与前列腺疾病起源的干细胞。
