Bis-phenol A: Signaling and Mitogenesis in the Prostate

描述（由申请人提供）：环境和商业流行 雌激素化合物（异种雌激素）已被分类为内分泌的 干扰物，或能够干扰正常激素功能的试剂， 人体暴露于异种雌激素已被证明会导致多种 生物学结果，如不育和发育缺陷。虽然 相当大的努力已经指向描绘的影响， 异种雌激素对女性生殖系统的影响，很少有研究探讨 这类药物对前列腺生长和维持的作用。 前列腺上皮细胞和原发性前列腺癌的细胞是 依赖于雄激素的增殖和存活。这种关键的依赖 前列腺对雄激素的作用被用于治疗前列腺疾病。 增生性疾病（例如良性前列腺增生和前列腺 腺癌）。越来越多的证据也表明雌激素在 前列腺细胞增殖。例如，暴露于雌激素 显示直接诱导前列腺增生动物模型系统。 此外，抗雌激素他莫昔芬在临床上用于减少前列腺 增长尽管有这些观察结果，雌激素刺激的机制 前列腺细胞生长尚未确定。此外， 还没有研究外源性雌激素对前列腺增殖和生长的影响。这里 我们发现，异雌激素双酚A（BPA）提供了不适当的 促有丝分裂刺激前列腺上皮细胞。这种促有丝分裂活性是 与核受体活性相关，并允许前列腺细胞绕过 对雄激素的需求根据我们的初步数据，我们假设 BPA激活前列腺细胞中的特定核受体， 不适当的促有丝分裂信号传导途径并启动细胞增殖。 BPA的这种作用可能促进前列腺增生的发展 和肿瘤形成。本文概述的实验将通过以下方式确定机制： BPA激活前列腺上皮细胞的核受体， BPA在这种细胞类型中的促有丝分裂信号通路，并评估其影响 这些药物对前列腺增生的形成和治疗的作用， 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.