Bis-phenol A: Signaling and Mitogenesis in the Prostate

描述(由申请人提供)：环境和商业上的流行 雌激素化合物(异种雌激素)被归类为内分泌。 干扰物，或能够扰乱体内正常荷尔蒙功能的物质 人体。暴露在外来雌激素下已被证明会导致不同的 生物学结果，如不孕不育和发育缺陷。虽然 已经做出了相当大的努力来描述 关于异种雌激素对女性生殖系统的影响，很少有研究研究 这类药物对前列腺的生长和维持的影响。 前列腺癌的前列腺上皮细胞和细胞 依赖雄激素进行增殖和存活。这种严重的依赖 前列腺雄激素在前列腺癌治疗中的应用 增生性疾病(例如良性前列腺增生症和前列腺 腺癌)。越来越多的证据也表明雌激素在 前列腺细胞的增殖。例如，与雌激素的接触一直是 显示可直接诱导前列腺增生症的动物模型系统。 此外，抗雌激素药物三苯氧胺在临床上用于减少前列腺癌。 成长。尽管有这些观察，雌激素刺激的机制 前列腺细胞的生长情况尚未确定。而且，它的效果是 异种雌激素对前列腺增殖和生长的影响尚未被探讨。这里 我们发现异种雌激素双酚A(BPA)提供了不适当的 对前列腺上皮细胞的促有丝分裂刺激作用。这种促有丝分裂活性是 与核受体活性有关，并允许前列腺细胞绕过 他们对雄激素的需求。根据我们的初步数据，我们假设 双酚A激活前列腺细胞中的特定核受体进行繁殖 不适当的有丝分裂信号通路和启动细胞增殖。 BPA的这种作用可能促进了前列腺增生症的发展 和肿瘤。本文概述的实验将通过以下方式确定该机制 哪种双酚A激活前列腺上皮细胞的核受体，定义 BPA在该细胞类型中的有丝分裂信号通路，并评估其影响 这些药物在前列腺增生症的形成和治疗中的作用 肿瘤。

DESCRIPTION (provided by applicant): Environmental and commercially prevalent estrogenic compounds (xenoestrogens) have been classified as endocrine disruptors, or agents capable of disrupting normal hormone function in the human body. Exposure to xenoestrogens has been shown to result in diverse biological outcomes, such as infertility and developmental defects. Although considerable effort has been directed toward delineating the effect of xenoestrogens on the female reproductive system, few studies have examined the effect of such agents on growth and maintenance of the prostate gland. Prostatic epithelia and the cells of primary prostatic adenocarcinomas are dependent on androgen for proliferation and survival. This critical dependence of the prostate on androgen is exploited in the treatment of prostatic proliferative diseases (e.g. benign prostatic hyperplasia and prostatic adenocarcinoma). Increasing evidence also demonstrates a role for estrogen in the prostate cell proliferation. For example, exposure to estrogen has been shown to directly induce prostate hyperplasia animal model systems. Additionally, the anti-estrogen Tamoxifen is used clinically to reduce prostate growth. Despite these observations, the mechanism by which estrogen stimulates prostate cell growth has not been determined. Moreover, the effect of xenoestrogens on prostate proliferation and growth has not been explored. Here we show that the xenoestrogen bis-phenol A (BPA) provides inappropriate mitogenic stimuli to prostatic epithelial cells. This mitogenic activity is associated with nuclear receptor activity, and allows prostate cells to bypass their requirement for androgen. Based on our preliminary data, we hypothesize that BPA activates specific nuclear receptors in prostate cells to propagate inappropriate mitogenic signaling pathways and initiate cellular proliferation. This action of BPA likely facilitates the development of prostate hyperplasias and neoplasias. The experiments outlined herein will determine the mechanism by which BPA activates nuclear receptors in prostate epithelia, define the mitogenic signaling pathway for BPA in this cell type, and assess the influence of these agents on the formation and treatment of prostate hyperplasias and neoplasias.