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

砷抑制孕激素受体信号传导并促进 ER 乳腺癌的他莫昔芬耐药性和转移

• 批准号: 10662054
• 负责人: Marcelo G Bonini
• 金额: $ 15万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10662054
• 关键词: Adjuvant; Adjuvant Therapy; Affect; Air Pollution; Alanine; Antineoplastic Agents; Antioxidants; Arsenic; Biosensor; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Treatment; Cadmium; Cell Line; Cell Nucleus; Cells; Chemoresistance; Communities; Critiques; Disease; Dose; Down-Regulation; Engineering; Environmental Exposure; Epigenetic Process; Epithelial; Estrogen Receptors; Exposure to; FDA approved; Felis catus; Frequencies; Gene Expression; Genes; Genetic; Goals; Health; Heavy Metals; Hydrogen Peroxide; International; Lead; Link; Low Income Population; Low income; Malignant Neoplasms; Mammary Neoplasms; Mesenchymal; Metal exposure; Metals; Metastatic/Recurrent; Minority; Minority Groups; Mitochondria; Modeling; Neoplasm Metastasis; Nuclear; Organelles; Outcome; Oxidases; Oxidation-Reduction; Particulate; Patients; Pharmacology; Phenotype; Poisoning; Pollution; Progesterone; Progesterone Receptors; Prognosis; Radiation therapy; Reactive Oxygen Species; Receptor Signaling; Refractory; Refractory Disease; Resistance; Risk; Selective Estrogen Receptor Modulators; Signal Transduction; Site; Source; System; Tamoxifen; Testing; Therapeutic; Treatment Effectiveness; Treatment Efficacy; Treatment outcome; Tumor Cell Nuclei; Water Supply; Woman; World Health; World Health Organization; Xenograft Model; Xenograft procedure; authority; base; catalase; cell transformation; chemotherapy; clinical biomarkers; design; environmental health disparity; hazard; improved; in vivo; in vivo monitoring; intravital microscopy; lead exposure; malignant breast neoplasm; marginalized population; mitochondrial dysfunction; molecular marker; neoplastic cell; novel; pollutant; radioresistant; socioeconomics; stem cells; toxic metal; tumor; tumor xenograft

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.

概括 该项目的中心概念是暴露现有的雌激素受体（ER）和 黄体酮（PR）阳性（ER+/PR+）乳腺肿瘤对重金属污染物的影响 缺乏 PR 表达和功能的肿瘤细胞的出现。而 ER+/PR+ 乳腺癌 具有良好的预后并对治疗反应良好，而 ER+/PR- 则不然，并且经常进展为 高致死率的复发性转移性疾病。因此，我们建议环境砷， 颗粒空气污染和供水中存在镉、铅或这些金属的混合物， 对 ER+/PR+ 乳腺癌女性的成功治疗构成严重风险 促进这些肿瘤重编程为 ER+/PR- 表型。此外，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。 随着细胞核中活性氧 (ROS) 的增加，很大程度上是由于重金属 引起线粒体功能障碍，孕激素受体基因表达受到抑制 释放表型重编程。我们还发现，从源头上淬灭这些 ROS （线粒体）或细胞核（作用位点）逆转 iAs 对 PR 表达的抑制， Cd 和 Pb 在很大程度上使金属转化的乳腺癌细胞对抗 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 针对低收入和少数民族人群的治疗。因为，我们现在已获得 FDA 批准，并且， 新型专利化合物可抑制肿瘤细胞中的核活性氧，这种策略可能会导致 迫切需要辅助疗法来减轻重度疾病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尤为严重。 因此，该项目的目标是：1）确定核ROS驱动的表观遗传如何 重编程影响 ER+/PR+ 肿瘤向治疗难治性 ER+/PR- 表型的转变； 2) 确定抑制细胞核中的 ROS 是否可以恢复异种移植的治疗效果 金属转化细胞的肿瘤模型； 3) 确定药理学是否获得 FDA 批准 线粒体 ROS 清除剂可有效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因素 接触重金属的影响可能是减少重金属影响的紧急短期解决方案 环境健康差异。