Arsenic suppresses progesterone receptor signaling and promotes tamoxifen resistance and metastasis of ER+ breast cancer

摘要 这个项目的中心概念是暴露现有的雌激素受体(ER)和 孕酮(PR)阳性(ER/PR)乳腺肿瘤对重金属污染物的促进作用 缺乏PR表达和功能的肿瘤细胞的出现。而ER/PR乳腺癌 预后良好，对治疗反应良好，ER/PR-不且经常进展为 高度致命的复发性转移性疾病。因此，我们认为环境中的砷， 镉、铅或这些金属的混合物存在于颗粒性空气污染和供水中， 对ER/PR乳腺癌患者的成功治疗构成严重风险 促进这些肿瘤重新编程为ER/PR表型。另外，我们发现， 重金属引起的表型重编程涉及细胞核氧化还原状态的变化。 由于重金属的作用，原子核中的活性氧物种(ROS)大量增加 导致线粒体功能障碍，孕激素受体基因表达受到抑制 释放表型重新编程。我们还发现，在原点猝灭这些ROS (线粒体)或在核(作用部位)逆转IAS对PR表达的抑制， Cd和Pd，并在很大程度上使金属转化的乳腺癌细胞对 一线选择性雌激素受体调节剂的肿瘤作用，通常是最容易获得的 针对低收入和少数群体的治疗。因为，我们现在有FDA批准的，以及， 新型专有化合物抑制肿瘤细胞中的核ROS，这一策略可能导致 迫切需要的辅助治疗来减轻重型肝炎对健康的一些最具破坏性的影响 金属污染物对低收入和少数族裔乳腺癌患者的影响不成比例。 因此，该项目的目标是：1)确定核ROS如何驱动表观遗传学 重新编程影响ER/PR肿瘤向治疗难治性ER/PR表型的转变； 2)确定抑制核内ROS是否能恢复异种移植的治疗效果 金属转化细胞的肿瘤模型；3)确定FDA批准的药理学 线粒体ROS清除剂有效地使金属转化的肿瘤细胞对 SERM。我们建议寻找药理学方法来减轻一些对健康有害的 暴露于重金属的影响可能是一个紧迫的短期解决方案，以减少 环境健康差距。

SUMMARY The central concept in this project is that exposure of existing estrogen receptor (ER) and progesterone (PR) positive (ER+/PR+) breast tumors to heavy metal pollutants promotes the emergence of tumor cells that lack PR expression and function. While ER+/PR+ breast cancer have excellent prognosis and respond well to treatments, ER+/PR- do not and often progress to highly lethal recurrent metastatic disease. Hence, we propose that environmental arsenic, cadmium, lead or mixtures of these metals present in particulate air pollution and water supplies, poses a grave risk for the successful treatment of women with ER+/PR+ breast cancer via promoting the reprogramming of these tumors to ER+/PR- phenotypes. In addition, we found that phenotypic reprogramming by heavy metals involves changes in the cellular nuclear redox state. As reactive oxygen species (ROS) increase in the nucleus, vastly because of heavy-metal induced mitochondrial dysfunction, progesterone receptor gene expression is suppressed unleashing phenotypic reprogramming. We also found that quenching these ROS at the origin (mitochondria) or in the nucleus (site of action) reverses the suppression of PR expression by iAs, Cd and Pb and to a large extent resensitizes metal-transformed breast cancer cells to the anti- neoplastic action of first line selective estrogen receptor modulators, often the most accessible therapy for low income and minority populations. Since, we now have FDA-approved, as well as, novel proprietary compounds to suppress nuclear ROS in tumor cells, this strategy may lead to much needed adjuvant therapies to mitigate some of the most devastating health effects of heavy metal contaminants disproportionately affecting low income and minority breast cancer patients. Therefore the goals of this project are: 1) Determine how nuclear ROS-driven epigenetic reprogramming impacts ER+/PR+ tumor transitions to treatment refractory ER+/PR- phenotypes; 2) Determine if suppressing ROS in the nucleus restores treatment effectiveness in xenograft tumor models of metal-transformed cells; 3) Determine if FDA-approved pharmacologic mitochondrial ROS scavengers are effective in resensitizing metal-transformed tumor cells to SERMs. We propose that finding pharmacologic ways to mitigate some ofthe detrimental health effects of exposures to heavy metals may be an urgent short term solution to reduce environmental health disparities.