Prolonged cadmium exposure promotes oxidative stress-dependent transcription and breast cancer progression

长期接触镉可促进氧化应激依赖性转录和乳腺癌进展

基本信息

批准号：
9015294
负责人：
Maggie C Louie
金额：
$ 40.51万
依托单位：
DOMINICAN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9015294
关键词：
Acute Air Animal Model Animals Behavior Binding Biological Process Breast Breast Cancer Cell Breast Cancer cell line Breast Carcinogenesis Cadmium Cell Proliferation Cells Chronic Clinical Coupled DNA Data Development Diet Dietary intake Disease Disease Progression Dose Endocrine Environmental Carcinogens Environmental Exposure Environmental Pollution Epidemiologic Studies Estrogen Receptor alpha Estrogen Receptors Estrogens Exposure to Food Contamination Genes Genetic Transcription Glutathione Goals Growth Hormones Human In Vitro Institution Investigation Lead Link MCF7 cell Malignant Neoplasms Mammary Neoplasms Mammary gland Masks Measurable Measures Microarray Analysis Molecular Mus Neoplasms Oncogenic Output Oxidative Stress Oxidative Stress Induction Pathological Staging Patient Self-Report Phenotype Phospholipids Physiological Prevention strategy Process Production Prostate Proteins Publishing Rattus Reactive Oxygen Species Receptor Signaling Reporting Research Proposals Research Training Risk Role Signal Transduction Testing Time Tissues Up-Regulation Water Weight Work biological adaptation to stress cancer prevention cancer risk cancer subtypes cell growth cigarette smoking density in vivo insight malignant breast neoplasm migration oxidative damage public health relevance receptor function tumor progression tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Cadmium is an environmental contaminant that enters the body through diet or cigarette smoke and accumulates in tissues over time, including those with endocrine functions, such as prostate and breast. Several studies in cells, including previous work from my lab, have shown that cadmium can mimic the functions of estrogen in breast cancer cells by activating the estrogen receptor (Garcia-Morales, et al. 1994, Stoica et al. 2000, Johnson et al. 2003, Martin et al. 2003, Byrne et al. 2009, Siewit et al. 2010). Findings from animal studies also suggest that cadmium can mimic the role of estrogen in vivo and promote neoplastic growth, increase uterine weight, induce changes in the uterine lining, and increase mammary gland density in rats and mice (Johnson et al. 2003, Alonso-Gonzalez et al. 2007, Hofer et al. 2009, Ali et al. 2008). These studies demonstrate that cadmium functions as a metalloestrogen and in this way is an important contributor to the development of breast cancer. In addition to acting as a metalloestrogen, acute cadmium exposure in vitro leads to glutathione depletion and leaves the cell vulnerable to "oxidative stress" through the decreased neutralization of reactive oxygen species (ROS). Oxidative stress is associated with transcriptional alterations leading to cancer development and progression. However, direct evidence of increased ROS levels or increased oxidative damage has not been evaluated in breast cancer cells exposed to cadmium, either in acute doses or environmentally relevant doses over prolonged periods of time. Though more relevant to understanding the effects of environmental cadmium exposure, the oxidative stress phenotypes associated prolonged exposure are not well-studied or consistently measurable, in part be due to adaptive tolerance mechanisms that may mask the actual effects of exposure. Adaptive tolerance is a key oncogenic mechanism, allowing unchecked cellular proliferation even in the presence of inherent cellular damage, thus increasing the tumorigenic and metastatic potential of breast cancer cells (Mahalingalah et al. 2014). Furthermore, induction of oxidative stress modifies estrogen receptor function and alters the clinical behavior of ER+ breast cancer cells (Yau et al. 2008), suggesting that oxidative stress may influence ER signalling to potentiate the carcinogenic functions of cadmium. Coupled with the data from our recent microarray analysis showing that a large number of genes deregulated in chronic cadmium- exposed cells are directly induced by oxidative stress, we hypothesize that at least part of the carcinogenic effects of cadmium exposure may be explained by cadmium-dependent oxidative stress and the upregulation of oxidative stress-response genes that may lead to adaptive tolerance and alter ER signaling in breast cancer cells. Here, we propose that chronic environmental exposure to cadmium induces oxidative stress-dependent transcription that promotes breast cancer progression. .

描述（由适用提供）：镉是一种环境污染物，通过饮食或香烟烟雾进入人体并随着时间的推移积聚在组织中，包括具有内分泌功能的人，例如前列腺和乳房。在包括我实验室的先前工作在内的细胞中的几项研究表明，镉可以通过激活雌激素受体来模仿雌激素在乳腺癌细胞中的功能（Garcia-Morales等，等1994，Stoica等。 2000年，约翰逊等。 2003年，Martin等。 2003年，伯恩等。 2009年，Siewit等。 2010）。动物研究的结果还表明，镉可以模仿雌激素在体内的作用并促进肿瘤生长，增加子宫体重，诱导子宫内衬的变化，并增加大鼠和小鼠的乳腺密度（Johnson等人2003，Alonso-Gonzalez等人，2007年，2007年，HOFER。这些研究表明，镉是甲基雌激素的作用，因此，镉是乳腺癌发展的重要原因。除了充当金属雌激素外，急性镉在体外暴露还会导致谷胱甘肽的部署，并通过改善反应性氧（ROS）的中和中和细胞容易受到“氧化应激”的影响。氧化应激与转录改变有关，导致癌症发展和进展。然而，在暴露于镉的乳腺癌细胞中，尚未评估ROS水平升高或氧化损伤增加的直接证据，无论是急性剂量还是在长时间的急性剂量或与环境相关的剂量中。尽管与了解环境镉暴露的影响更加相关，但与长时间暴露相关的氧化应激表型并非经过充分研究或始终如一的测量，部分是由于适应性耐受性机制，可能掩盖了现实的暴露效果。自适应耐受性是一种关键的致癌机制，即使在存在遗传性细胞损伤的情况下，也允许未经检查的细胞增殖，从而增加了乳腺癌细胞的肿瘤性和转移性潜力（Mahalingalah等人，2014年）。此外，诱导氧化应激修饰剂雌激素受体功能并改变ER+乳腺癌细胞的临床行为（Yau等，2008），这表明氧化物应激可能影响ER信号对镉的致癌功能影响。再加上我们最近的微阵列分析中的数据，表明在慢性镉暴露细胞中失调的大量基因被氧化物胁迫直接诱导，我们假设至少有一部分致癌作用镉暴露可以通过镉依赖性氧化应激以及氧化应激反应基因的上调来解释，这可能导致适应性耐受性并改变乳腺癌细胞中的ER信号传导。在这里，我们建议慢性环境暴露于镉会诱导氧化应激依赖性转录，从而促进乳腺癌的进展。