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

 描述(申请人提供)：镉是一种环境污染物，通过饮食或香烟烟雾进入人体，并随着时间的推移在组织中积累，包括具有内分泌功能的组织，如前列腺和乳房。对细胞的几项研究，包括我实验室以前的工作，已经表明镉可以通过激活雌激素受体来模拟乳腺癌细胞中雌激素的功能(Garcia-Morales等人)。1994年，Stoica等人。 2000年，Johnson等人提出的。2003年，Martin等人提出。2003年，Byrne等人。2009年，Siewit等人。2010)。动物研究的结果还表明，镉可以在体内模拟雌激素的作用，促进大鼠和小鼠的肿瘤生长，增加子宫重量，诱导子宫内层的变化，并增加乳腺密度(Johnson等人)。2003年，阿隆索-冈萨雷斯等人。2007年，Hofer等人。2009年，Ali等人。2008年)。这些研究表明，镉作为一种金属雌激素，在这种情况下是乳腺癌发生的重要因素。除了作为一种金属雌激素，急性镉暴露在体外会导致谷胱甘肽耗竭，并通过减少活性氧物种(ROS)的中和而使细胞容易受到“氧化应激”的影响。氧化应激与导致癌症发生和发展的转录改变有关。然而，无论是急性剂量还是与环境相关的剂量，长期暴露于镉的乳腺癌细胞中，ROS水平增加或氧化损伤增加的直接证据尚未得到评估。虽然与理解环境镉暴露的影响更相关，但与长期暴露相关的氧化应激表型没有得到很好的研究或一致地测量，部分原因是适应性耐受机制可能掩盖了暴露的实际影响。适应性耐受是一个关键的致癌机制，即使在存在固有的细胞损伤的情况下也允许不受控制的细胞增殖，从而增加乳腺癌细胞的致瘤和转移潜力(Mahalingalah等人)。2014年)。此外，氧化应激的诱导改变了雌激素受体的功能，并改变了ER+乳腺癌细胞的临床行为(Yau等人。2008)，这表明氧化应激可能影响内质网信号转导，以增强镉的致癌功能。结合我们最近的微阵列分析数据显示，在慢性镉暴露的细胞中，大量被解除调控的基因是由氧化应激直接诱导的，我们假设至少部分致癌作用 镉暴露的原因可能是镉依赖的氧化应激和氧化应激反应基因的上调，这些基因可能导致乳腺癌细胞的适应性耐受并改变ER信号。在这里，我们认为，慢性环境接触镉诱导氧化应激依赖的转录，从而促进乳腺癌的进展。。

 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. .