Telomere shortening has been demonstrated in benign prostatic hypertrophy (BPH), which is associated with prostate epithelial cell senescence. Telomere shortening is the most frequently observed genetic alteration in prostatic intraepithelial neoplasia, and is associated with poor clinical outcomes in prostate cancer. Gene expression database analysis revealed decreased TRF2 expression during malignant progression of the prostate gland. We reasoned that reduced TRF2 expression in prostate epithelium, by activating the telomere DNA damage response, would allow us to model both benign and malignant prostate disease. Prostate glands with reduced epithelial TRF2 expression developed age- and p53-dependent hypertrophy, senescence, ductal dilation, and smooth muscle hyperplasia similar to human BPH. Prostate tumors with reduced TRF2 expression were classified as high-grade androgen receptor–negative adenocarcinomas, which exhibited decreased latency, increased proliferation, and distant metastases. Prostate cancer stem cells with reduced TRF2 expression were highly tumorigenic and maintained telomeres both by telomerase and alternative lengthening (ALT). Telomerase inhibition in prostate glands with reduced TRF2 expression produced significant reduction in prostate tumor incidence by halting progression at intraepithelial neoplasia (PIN). These lesions were highly differentiated, exhibited low proliferation index, and high apoptotic cell fraction. Prostate tumors with reduced TRF2 expression and telomerase inhibition failed to metastasize and did not exhibit ALT. Implications: Our results demonstrate that the telomere DNA damage response regulates BPH, PIN, and prostate cancer and may be therapeutically manipulated to prevent prostate cancer progression.

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端粒 DNA 损伤信号调控前列腺癌的发生

端粒缩短已在与前列腺上皮细胞衰老相关的良性前列腺肥大 (BPH) 中得到证实。端粒缩短是前列腺上皮内瘤变中最常观察到的基因改变，并且与前列腺癌的不良临床结果相关。基因表达数据库分析显示前列腺恶性进展期间 TRF2 表达降低。我们推断，通过激活端粒 DNA 损伤反应，降低前列腺上皮中 TRF2 的表达将使我们能够模拟良性和恶性前列腺疾病。具有降低的上皮 TRF2 表达的前列腺发展为年龄和 p53 依赖性肥大、衰老、导管扩张和平滑肌增生，类似于人类 BPH。TRF2 表达降低的前列腺肿瘤被归类为高级别雄激素受体阴性腺癌，其表现出潜伏期减少、增殖增加和远处转移。TRF2 表达降低的前列腺癌干细胞具有高度的致瘤性，并通过端粒酶和替代延长 (ALT) 维持端粒。TRF2 表达降低的前列腺中的端粒酶抑制通过阻止上皮内瘤变 (PIN) 的进展而显着降低了前列腺肿瘤的发生率。这些病变高度分化，表现出低增殖指数和高凋亡细胞分数。具有降低的 TRF2 表达和端粒酶抑制的前列腺肿瘤未能转移并且没有表现出 ALT。含义：