NBL 大鼠前列腺中的激素和遗传毒性雌激素-雄激素致癌作用：芳香酶的作用。

Hormonal and genotoxic estrogen-androgen carcinogenesis in the NBL rat prostate: A role for aromatase.

机构信息

Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, USA.

Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA.

出版信息

Prostate. 2023 Jun;83(9):823-830. doi: 10.1002/pros.24522. Epub 2023 Mar 20.

DOI:10.1002/pros.24522

PMID:36938936

Abstract

BACKGROUND

Androgens are generally thought to cause prostate cancer, but the data from animal studies suggest that they must be aromatized to estrogen and act in concert with genotoxic estrogen metabolites. The objective of this study was to determine whether treatment with testosterone (T) combined with a nonestrogenic estrogen metabolite and a nongenotoxic estrogenic compound would all be necessary and sufficient for the induction of a high incidence of prostate cancer in the susceptible NBL rat strain.

METHODS

NBL rats were treated with low-dose testosterone via slow-release Silastic implants and with the marginally estrogenic genotoxic catechol estrogen 4-hydroxyestradiol (4OH-E2) and the nongenotoxic estrogen 2-fluoroestradiol (2F-E2) and in one experiment the aromatase inhibitor letrozole via custom-made slow-release pellets. Animals were euthanized 52 weeks after implantation and their pituitaries and prostate complexes weighed and fixed in formalin. Hematoxylin and eosin (H&E)-stained step sections were prepared and examined microscopically for proliferative lesions.

RESULTS

Animals treated with 2F-E2, with or without the other compounds, had enlarged pituitaries demonstrating its estrogenicity. Animals treated with T, with or without the other compounds, had enlarged prostates consistent with its androgenicity. Rats treated with T plus 2F-E2 and 4OH-E2 developed a high incidence of prostatic cancer (89%), while, surprisingly, rats treated with T plus only 2F-E2 also had a high incidence of prostate cancer (95%) contradicting our initial hypothesis. To test whether the formation of E2 from T by aromatase could lead to estrogen genotoxicity and prostate carcinogenesis we then rats treated with T and 2F-E2 also with letrozole and found that it reduced prostate cancer incidence by about 50%.

CONCLUSIONS

These findings indicate that long-term treatment with a nongenotoxic estrogen (2F-E2) and T as well as uninhibited prostatic aromatase activity generating genotoxic E2 are all required for induction of a high incidence of prostatic adenocarcinomas in NBL rats. These and previous data indicate that androgen receptor-mediated action, estrogen receptor mediation, and estrogen genotoxicity are all required and sufficient for hormonal carcinogenesis in the NBL rat prostate. Interference with the estrogen genotoxicity is a potential approach to prostate cancer chemoprevention.

摘要

背景

雄激素通常被认为会导致前列腺癌，但动物研究的数据表明，它们必须被芳香化为雌激素，并与致基因突变的雌激素代谢物协同作用。本研究的目的是确定在易感 NBL 大鼠品系中，联合使用睾酮（T）、非雌激素性雌激素代谢物和非致基因突变的雌激素化合物是否都有必要且足以诱导前列腺癌的高发病率。

方法

通过慢释放硅橡胶植入物给予 NBL 大鼠低剂量 T，并给予边缘雌激素致基因突变的儿茶酚雌激素 4-羟基雌二醇（4OH-E2）和非致基因突变的雌激素 2-氟雌二醇（2F-E2），在一个实验中还通过定制的慢释放丸给予芳香酶抑制剂来曲唑。植入后 52 周时处死动物，称重并将其垂体和前列腺复合体固定在福尔马林中。制备并检查苏木精和伊红（H&E）染色的连续切片，以检查增殖性病变。

结果

用 2F-E2、用或不用其他化合物治疗的动物，其垂体增大，表明其具有雌激素性。用 T、用或不用其他化合物治疗的动物，其前列腺增大，表明其具有雄激素性。用 T 加 2F-E2 和 4OH-E2 治疗的大鼠，前列腺癌的发病率很高（89%），但令人惊讶的是，用 T 加仅 2F-E2 治疗的大鼠，前列腺癌的发病率也很高（95%），这与我们最初的假设相矛盾。为了测试 T 通过芳香酶转化为 E2 是否会导致雌激素致基因突变和前列腺癌发生，我们随后用 T 和 2F-E2 治疗大鼠，同时也用来曲唑治疗，并发现它使前列腺癌的发病率降低了约 50%。

结论

这些发现表明，长期使用非致基因突变的雌激素（2F-E2）和 T 以及不受抑制的前列腺芳香酶活性生成致基因突变的 E2，对于诱导 NBL 大鼠中前列腺腺癌的高发病率都是必要且充分的。这些和以前的数据表明，雄激素受体介导的作用、雌激素受体介导的作用和雌激素致基因突变，对于 NBL 大鼠前列腺的激素致癌作用都是必要且充分的。干扰雌激素致基因突变是前列腺癌化学预防的一种潜在方法。