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 该项目的核心概念是暴露于现有的雌激素受体（ER）和 重金属污染物的孕酮（PR）阳性（ER+/PR+）乳腺肿瘤促进 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，对治疗的反应很好，ER+/pr-不及 高度致命的复发转移性疾病。因此，我们提出了环境砷， 这些金属的镉，颗粒空气污染和供水中存在的铅或混合物， 通过通过ER+/PR+乳腺癌成功治疗成功治疗的严重风险 将这些肿瘤重编程为ER+/PR-表型。此外，我们发现 重金属的表型重编程涉及细胞核氧化还原状态的变化。 随着活性氧（ROS）在细胞核中的增加，大大是由于重金属 诱导的线粒体功能障碍，孕激素受体基因表达被抑制 释放表型重编程。我们还发现，将这些ROS淬灭。 （线粒体）或核中（作用部位）在IAS中逆转PR表达的抑制， CD和PB，并且在很大程度上使金属转化的乳腺癌细胞归功于抗 第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 低收入和少数族裔的治疗。从那以后，我们现在已经进行了FDA批准的以及 新型专有化合物可抑制肿瘤细胞中的核ROS，该策略可能导致 急需的辅助疗法可以减轻重型的一些最具破坏性的健康影响 金属污染物不成比例地影响低收入和少数乳腺癌患者。 因此，该项目的目标是：1）确定核ROS驱动的表观遗传学如何 重编程会影响ER+/PR+肿瘤过渡到治疗难治性ER+/PR-表型； 2）确定抑制核中的ROS是否恢复异种移植物的治疗效果 金属转化细胞的肿瘤模型； 3）确定FDA批准的药理学是否 线粒体ROS清除剂可有效地将金属转化的肿瘤细胞恢复到 Serms。我们建议寻找药理方法来减轻某些有害健康 暴露于重金属的影响可能是一种紧急的短期解决方案，以减少 环境健康差异。