Chronic Cadmium Exposure Promotes Breast Cancer Progression

描述(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。乳腺癌是由乳腺的异常生长引起的，乳腺受到女性荷尔蒙--雌激素的调节。雌激素的活性是由雌激素受体(ER)介导的，而ER又调节乳腺生长发育所必需的基因的表达。ER的存在或缺失是乳腺癌发生发展的一个关键的预后标志。大多数乳腺癌最初的发展依赖于激素，这意味着雌激素的存在可以促进癌症的进展。然而，激素敏感型乳腺癌经常发展成更具侵袭性的不依赖激素的表型。在许多情况下，ER仍然存在，但它在激素难治性肿瘤发生中的作用尚不清楚。激素难治性乳腺癌的一个潜在机制可能涉及内分泌干扰物，包括重金属，如镉。镉是一种环境污染物，通过饮食或香烟烟雾进入人体。它影响多种细胞过程，包括细胞的增殖、分化和凋亡。多项研究表明，镉具有金属雌激素的作用，并具有结合和激活ER1的能力。我们自己和其他研究人员最近的研究表明，镉可以刺激ER靶基因的表达。此外，我们还证明了镉增强了ER1和c-jun等转录因子之间的分子串扰，从而调节了镉诱导基因的表达。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。由于这些重金属往往会在生物中积累，因此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，接触镉与更多恶性肿瘤的发生有关。我的实验室的初步发现还表明，慢性镉暴露可以促进乳腺癌细胞的生长和迁移。这让我假设，长期接触镉可能会促进更具侵袭性的乳腺癌的发展。这项研究的结果将使我们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。这项研究的结果将对临床做出重大贡献，包括筛选重金属毒性，识别与重金属相关的乳腺癌病例，开发暴露于高浓度镉的肿瘤的表达谱，以及设计更有效的激素耐药乳腺癌病例的治疗方法。 公共卫生相关性：这项研究的目标是1)表征慢性镉暴露对乳腺癌进展的影响，2)确定镉水平与肿瘤病理之间是否存在相关性，以及3)确定与长期接触镉的癌细胞相关的基因表达谱。这项研究的结果不仅将更好地了解长期接触环境污染物(如镉)如何促进乳腺癌的进展，还将为其作用机制提供新的见解。此外，这项研究的结果将对临床做出重大贡献，包括筛选重金属毒性，识别与重金属相关的乳腺癌病例，开发暴露于高镉水平的肿瘤的表达谱，以及设计更有效的激素耐药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.