Estrogen receptor mediated reprogramming of prostate in BPH

雌激素受体介导的良性前列腺增生症前列腺重编程 保罗·S·库克和盖尔·S·普林斯，多PI 摘要 在关键发育期暴露于雌激素可以永久性地重新编程前列腺 腺体，导致成人生活中的生长异常，包括间质和上皮增生，良性 腺瘤和慢性前列腺炎。因此，我们认为早期雌激素暴露可能是一种 老年男性良性前列腺增生症的易感因素。过去的工作已经确定 表观遗传修饰是前列腺发育重新编程的基础；然而， 导致这种表观基因组重组的原因尚不清楚。我们先前已经证明雌激素受体1(ESR1； 也称为ERα)对于这种重新编程是必要和充分的；然而，不同的信号通路 通过膜ESR1(MESR1)或核ESR1(NESR1)启动的作用尚不清楚。我们的 新公布的初步数据揭示了mESR1在正常男性生殖中的重要作用 发育和生育，以及正常的前列腺对发育雌激素的反应。此外，一个 最近的报告发现，重要的表观遗传学变化可能导致某些基因的高反应性 参与生长和细胞增殖的分子可通过mESR1信号通路在发育过程中启动 前列腺癌。在这方面，拟议研究的目标是描绘mESR1和mESR1的相对作用 NESR1在调节发育期雌激素重编程中的作用及鉴定其利用的“非基因组”途径 MESR1对腺体内的表观记忆进行重新编程，包括前列腺上皮干细胞。在此，我们 将采用一种创新的方法，通过利用新开发的 正常表达nESR1但缺乏mESR1信号的敲入小鼠模型(仅有核的ESR1小鼠； NOER)或表达mESR1及其下游信号通路但缺乏nESR1(H2NES小鼠)。 这些强大而独特的新模型使我们能够采取直接的实验方法来梳理出 ESR1在细胞表观遗传印记中的特殊作用(S) 前列腺癌，这在以前是不可能的。为了实现这些目标，我们提出了三个具体目标 目标。目标1：确定mESR1对于雌激素驱动的发育是否必要和/或充分 前列腺重编程。目的2：确定雌激素诱导的表观遗传印迹中的信号级联反应。 目的3：阐明mESR1和nESR1在前列腺干/祖细胞重编程中的作用。这个 拟议的研究将填补关于mESR1和nESR1在前列腺中的不同作用的知识空白 发展和拓宽前列腺癌雌激素印迹的机制基础。总之，结果是 将提供关于雌激素通过mESR1和mESR1的作用的新的和临床相关的见解 和nESR1在推动BPH中的作用，并为未来可以针对膜启动的药物发现策略提供信息 前列腺中的雌激素信号。

ESTROGEN RECEPTOR MEDIATED REPROGRAMMING OF THE PROSTATE IN BPH Paul S. Cooke and Gail S Prins, Multi-PIs Abstract Exposure to estrogens during critical developmental periods can permanently reprogram the prostate gland, resulting in growth abnormalities in adult life that include stromal and epithelial hyperplasia, benign adenomas and chronic prostatitis. As such, we propose that early-life estrogenic exposures may be a predisposing factor for benign prostatic hyperplasia (BPH) in aging males. Past work has established that epigenetic modifications underpin developmental reprogramming of the prostate; however, the pathways that lead to this epigenomic reorganization are unclear. We previously showed that estrogen receptor 1 (ESR1; also known as ERα) is essential and sufficient for this reprogramming; however, distinct signaling pathways initiated through membrane ESR1 (mESR1) or nuclear ESR1 (nESR1) actions have not been clarified. Our new published and preliminary data now reveal essential roles for mESR1 in normal male reproductive development and fertility, as well as the normal prostatic response to developmental estrogenization. Further, a recent report found that important epigenetic changes that could lead to hyperresponsivity of certain genes involved in growth and cell proliferation can be initiated through mESR1 signaling cascades in the developing prostate gland. In this context, the goals of the proposed research are to delineate relative roles of mESR1 and nESR1 in mediating developmental estrogen reprogramming and to identify “nongenomic” pathways utilized by mESR1 to reprogram epigenomic memory within the gland, including prostate epithelial stem cells. Herein, we will take an innovative approach to directly interrogate mESR1 and nESR1 actions by utilizing newly developed knock-in mouse models that express nESR1 normally but lack mESR1 signaling (nuclear-only ESR1 mouse; NOER) or that express mESR1 and its downstream signaling pathways but lack nESR1 (H2NES mouse). These powerful and unique new models allow us to take a direct experimental approach to tease out the specific role(s) for ESR1 in each compartment and their downstream effectors on epigenetic imprinting in the prostate, which has previously not been possible. Three Specific Aims are proposed to accomplish these goals. Aim 1: Establish whether mESR1 is necessary and/or sufficient for estrogen-driven developmental prostate reprogramming. Aim 2: Identify signaling cascades involved in estrogen-induced epigenetic imprinting. Aim 3: Elucidate the roles of mESR1 and nESR1 in reprogramming prostate stem/progenitor cells. The proposed studies will fill knowledge gaps on the differential roles of mESR1 and nESR1 in prostate development and broaden the mechanistic basis for estrogenic imprinting in the prostate. Together, the results will provide new and clinically relevant insights regarding the role of estrogen signaling through both mESR1 and nESR1 in driving BPH and inform future drug discovery strategies that can target membrane-initiated estrogen signaling in the prostate.