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

 描述（由申请人提供）：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，如前列腺和乳腺。在细胞中的几项研究，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，1999年）。 2000，约翰逊等人2003，马丁等人2003，伯恩等人2009，Siewit等人2010）。动物研究的结果还表明，镉可以模拟体内雌激素的作用，促进肿瘤生长，增加子宫重量，诱导子宫内膜变化，并增加大鼠和小鼠的乳腺密度（约翰逊等人，2003年; Alonso-Gonzalez等人，2007年;霍费尔等人，2009年; Ali等人，2008年）。这些研究表明，镉作为一种金属雌激素发挥作用，并以这种方式成为乳腺癌发展的重要因素。除了作为一种金属雌激素，急性镉暴露在体外导致谷胱甘肽耗竭，并离开细胞容易受到“氧化应激”通过减少中和活性氧（ROS）。氧化应激与导致癌症发展和进展的转录改变相关。然而，在暴露于镉的乳腺癌细胞中，无论是急性剂量还是长期环境相关剂量，都没有评估ROS水平增加或氧化损伤增加的直接证据。虽然更相关的理解环境镉暴露的影响，氧化应激表型相关的长期暴露没有得到很好的研究或一致的测量，部分是由于适应性耐受机制，可能掩盖了暴露的实际影响。适应性耐受是一种关键的致癌机制，即使在存在固有细胞损伤的情况下也允许不受抑制的细胞增殖，从而增加乳腺癌细胞的致瘤性和转移潜力（Mahalingalah et al. 2014）。此外，氧化应激的诱导改变了雌激素受体功能，并改变了ER+乳腺癌细胞的临床行为（Yau et al. 2008），表明氧化应激可能影响ER信号传导，从而增强镉的致癌功能。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，大量的基因失调是由氧化应激直接诱导的，我们假设至少部分致癌作用是由氧化应激引起的。 镉依赖性氧化应激和氧化应激反应基因的上调可能导致适应性耐受和改变乳腺癌细胞中的ER信号传导，在这里，我们提出，慢性环境暴露于镉诱导氧化应激依赖的转录，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. .