Understanding Progesterone Receptor action in Obesity for Endometrial Cancer Prevention

子宫内膜癌的发病率每年都在上升，2018年美国的新发病例超过60，000例。肥胖仍然是一个重要的公共卫生问题，也是发生子宫内膜癌的主要危险因素。虽然脂肪组织中过量的雌激素被认为是妇女患子宫内膜癌的易感因素，但孕激素在肥胖中的保护作用尚不清楚。研究表明，过量雌激素理论在肥胖妇女并不总是正确的，特别是在绝经前的状态。我们假设脂肪组织释放的因子激活子宫内膜上皮细胞中的AKT通路，从而减弱孕激素受体（PR）的作用，从而增加子宫内膜肿瘤的风险。在这项研究中，我们将使用微流控系统中的3D球体培养物，在脂肪细胞存在或不存在的情况下，破译PR在人类子宫内膜中的作用。这些创新技术使我们能够首次研究脂肪细胞对影响孕酮敏感性的信号传导和基因组活动的影响。我们将确定脂肪细胞如何影响孕激素驱动的子宫内膜类器官的分化和存活，以及表观遗传学的变化，包括DNA甲基化和组蛋白标记，如何影响ER和PR顺式组。将使用允许对小细胞数量进行深度测序的技术进行无偏测序。这项研究将深入了解可能导致肿瘤发生的早期变化，这将有助于确定如何有效预防高危肥胖妇女的子宫内膜癌。

The incidence of endometrial cancer is on the rise each year reaching over 60,000 new cases in the US in 2018. Obesity remains a significant public health problem and is a major risk factor for developing endometrial cancer. Although excess estrogen from adipose tissues is thought to predispose a woman from developing endometrial cancer, the protective role of progesterone in obesity is unknown. Studies demonstrate that the excess estrogen theory in obese women does not always hold true particularly in the premenopausal state. We hypothesize that adipose tissue release factors that activate the AKT pathway in endometrial epithelial cells to blunt progesterone receptor (PR) action, thereby increasing the risk of endometrial neoplasia. In this study, we will decipher the actions of PR in the human endometrium in the presence or absence of adipocytes using 3D spheroid cultures in microfluidic systems. These innovative technologies allow us to study for the first time, the effect of adipocytes on the signaling and genomic activities that affect progesterone sensitivity. We will determine how adipocytes affect progesterone driven differentiation and survival of the endometrial organoids and how changes in epigenetics, including DNA methylation and histone marks, affect the ER and PR cistrome. Unbiased sequencing will be done using technologies that allow for deep sequencing of small cell numbers. This research will generate insight into the early changes that may lead to tumorigenesis which will be useful to determine how to effectively prevent endometrial cancer in the obese women who are at high risk.