Chronic Cadmium Exposure Promotes Breast Cancer Progression

描述（由申请人提供）：乳腺癌是美国女性最常见的癌症之一；它占女性癌症的四分之一，使其成为西方世界最重要的癌症之一。乳腺癌是由受雌性激素雌激素调节的乳腺异常生长引起的。雌激素的活性是由雌激素受体（ER）介导的，雌激素受体反过来调节乳腺生长发育所需基因的表达。雌激素受体的存在与否是乳腺癌发展的关键预后指标。大多数乳腺癌最初发展为激素依赖，这意味着雌激素的存在可以促进癌症的发展。然而，激素反应性乳腺癌经常发展成更具侵略性的表型，这些表型与激素无关。在许多病例中，ER仍然存在，但其在激素难治性肿瘤发生中的作用尚不清楚。激素难治性乳腺癌发生的潜在机制可能与内分泌干扰物有关，包括镉等重金属。镉是一种通过饮食或香烟烟雾进入人体的环境污染物。它影响多种细胞过程，包括细胞增殖、分化和凋亡。几项研究表明，镉具有金属雌激素的功能，并能结合和激活ER1。我们自己和其他人的研究最近表明，镉可以刺激内质网靶基因的表达。此外，我们已经证明，镉增强ER1和转录因子如c-jun之间的分子串扰，以调节镉诱导基因的表达。虽然已知急性镉暴露会激活雌激素受体并促进细胞生长，但慢性镉暴露的后果尚不清楚。由于这些重金属倾向于生物积累，有必要了解和阐明长期接触镉对乳腺癌进展的影响。研究表明，接触镉与恶性肿瘤的发展有关。我实验室的初步研究结果还表明，长期接触镉可以促进乳腺癌细胞的生长和迁移。这让我猜测，长期接触镉可能会促进更具侵袭性的乳腺癌的发展。这项研究的结果将更好地了解镉如何促进乳腺癌的进展，并为其作用机制提供见解。从这项研究中获得的结果将具有重要的临床贡献，包括筛选重金属毒性，识别重金属相关的乳腺癌病例，开发暴露于高浓度镉的肿瘤表达谱，以及设计更有效的激素难治性乳腺癌病例的治疗方法。

DESCRIPTION (provided by applicant): Breast cancer is among one of the most common cancers that occur in women in the United States; it accounts for one in four female cancers, making it one of the most important cancers in the Western world. Breast cancer results from the abnormal growth of the mammary gland, which is regulated by the female hormone, estrogen. The activity of estrogen is mediated by the estrogen receptor (ER) which in turn regulates the expression of genes necessary for the growth and development of the mammary gland. The presence or absence of the ER serves as a key prognostic marker in breast cancer development. The majority of breast cancers initially develop as hormone dependent, which implies that the presence of estrogen can enhance the progression of the cancer. However, hormone responsive breast cancers frequently develop into more aggressive phenotypes that are hormone independent. In many cases, the ER is still present, but its role in hormone refractory tumorigenesis is unclear. A potential mechanism for the development of hormone refractory breast cancer may involve endocrine disruptors, including heavy metals such as cadmium. Cadmium is an environmental contaminant that enters the body through the diet or cigarette smoke. It affects multiple cellular processes, including cell proliferation, differentiation and apoptosis. Cadmium has been implicated by several studies to function as a metalloestrogen and has the ability to bind and activate ER1. Our own studies along with others have recently shown that cadmium can stimulate ER target gene expression. Additionally, we have demonstrated that cadmium potentiates the molecular cross-talk between ER1 and transcription factors like c-jun to regulate the expression of cadmium-induced genes. While acute cadmium exposure is known to activate the estrogen receptor and promote cell growth, the consequence of chronic cadmium exposure is unclear. Since these heavy metals tend to bioaccumulate, it is necessary to understand and elucidate the effects of prolonged cadmium exposure on breast cancer progression. Studies have shown that exposure to cadmium is associated with development of more malignant tumors. My lab's preliminary findings also suggest that chronic cadmium exposure can enhance breast cancer cell growth and migration. This leads me to hypothesize that chronic cadmium exposure may promote the development of more aggressive breast cancer. Results from this study will provide a better understanding of how cadmium contributes to the progression of breast cancer and offer insights into its mechanism of action. Results obtained from this research will have significant clinical contributions, including screening for heavy metal toxicities, identifying heavy metal-associated breast cancer cases, developing expression profiles of tumors exposed to high concentrations of cadmium, and designing more effective treatments for hormone- refractory breast cancer cases. PUBLIC HEALTH RELEVANCE: The objectives of this study are to 1) characterize the effects of chronic cadmium exposure on the progression of breast cancer, 2) determine if there is a correlation between cadmium levels and tumor pathology, and 3) identify the gene expression profile associated with cancer cells exposed to prolonged periods of cadmium. Results from this study will not only provide a better understanding of how prolonged exposure of environmental contaminants such as cadmium can promote breast cancer progression, but also offer new insights into the mechanism of action. Additionally, the results obtained from this research will have significant clinical contributions, including screening for heavy metal toxicities, identifying heavy metal-associated breast cancer cases, developing expression profiles of tumors exposed to high cadmium levels, and designing more effective treatments for hormone-refractory breast cancer cases.