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



 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. .