Chronic Cadmium Exposure Promotes Breast Cancer Progression

长期接触镉会促进乳腺癌进展

• 批准号: 8521009
• 负责人: Maggie C Louie
• 金额: $ 5.3万
• 依托单位: DOMINICAN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-21 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8521009
• 关键词: Ablation; Accounting; Acute; Affect; Apoptosis; Binding; Biological Sciences; Breast Cancer Cell; Cadmium; Cancer Cell Growth; Cell Culture Techniques; Cell Proliferation; Cell physiology; Cells; Cessation of life; Characteristics; Chronic; Clinical; Collaborations; Cyclin D1; Data; Development; Diet; Disease; Education; Endocrine Disruptors; Endocrinology; Environmental Pollution; Estrogen Antagonists; Estrogen Receptor Modulators; Estrogen Receptors; Estrogens; Exposure to; Female; Gene Expression; Gene Expression Profile; Genes; Growth; Growth and Development function; Heavy Metals; Hormone Responsive; Hormones; Incidence; Institution; JUN gene; Link; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Mediating; Modeling; Molecular; Molecular Profiling; Mus; Neoplasm Metastasis; Neoplasms; Pathological Staging; Phase; Phenotype; Prognostic Marker; Refractory; Research; Research Personnel; Research Project Grants; Research Proposals; Research Training; Role; Screening procedure; Social Interaction; Students; Techniques; Tumor Pathology; United States; Western World; Woman; assault; breast tumorigenesis; c-myc Genes; cancer cell; career; cell growth; cell motility; cigarette smoking; design; effective therapy; experience; exposed human population; insight; malignant breast neoplasm; metal poisoning; public health relevance; therapeutic target; transcription factor; tumor; tumor progression; tumorigenesis

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.

描述（由申请人提供）：乳腺癌是美国女性最常见的癌症之一；它占四分之一的雌性癌症，使其成为西方世界上最重要的癌症之一。乳腺癌是由乳腺异常生长引起的，乳腺受到雌性激素雌激素的调节。雌激素的活性是由雌激素受体（ER）介导的，雌激素受体（ER）又调节了乳腺生长和发育所必需的基因的表达。 ER的存在或不存在是乳腺癌发育中的关键预后标记。大多数乳腺癌最初以激素依赖性发展，这意味着雌激素的存在可以增强癌症的进展。然而，激素反应性乳腺癌经常发展为激素独立的更具侵略性的表型。在许多情况下，ER仍然存在，但是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展的潜在机制可能涉及内分泌干扰物，包括重金属，例如镉。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。镉已经与多项研究有关，以充当金属雌激素，并具有结合和激活ER1的能力。我们自己的研究以及其他研究最近表明，镉可以刺激ER靶基因表达。此外，我们已经证明镉增强了ER1与C-Jun（例如C-Jun）之间的分子串扰，以调节镉诱导的基因的表达。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蓄积，因此有必要理解和阐明长时间镉暴露对乳腺癌进展的影响。研究表明，暴露于镉与更恶性肿瘤的发展有关。我实验室的初步发现还表明，慢性镉暴露可以增强乳腺癌细胞的生长和迁移。这使我假设慢性镉暴露可能会促进更具侵略性的乳腺癌的发展。这项研究的结果将更好地了解镉如何促进乳腺癌的发展，并提供对其作用机理的见解。从这项研究获得的结果将具有重大的临床贡献，包括筛查重金属毒性，确定重金属相关的乳腺癌病例，发展暴露于高浓度镉的肿瘤的表达谱以及为激素 - 耐受性乳腺癌病例设计更有效的治疗方法。 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学之间是否存在相关性，以及3）确定与暴露于延长钙的癌细胞相关的基因表达谱。这项研究的结果不仅可以更好地了解诸如镉等环境污染物的长时间暴露可以促进乳腺癌的进展，而且还为作用机理提供了新的见解。此外，从这项研究中获得的结果将具有重大的临床贡献，包括筛查重金属毒性，鉴定与重金属相关的乳腺癌病例，形成暴露于高镉水平的肿瘤的表达谱，以及为激素难治性乳腺癌病例设计更有效的治疗方法。

项目成果

The role of cadmium and nickel in estrogen receptor signaling and breast cancer: metalloestrogens or not?

• DOI: 10.1080/10590501.2012.705159
• 发表时间: 2012
• 期刊: Journal of environmental science and health. Part C, Environmental carcinogenesis & ecotoxicology reviews
• 作者: Aquino NB;Sevigny MB;Sabangan J;Louie MC
• 通讯作者: Louie MC

Using expression profiling to understand the effects of chronic cadmium exposure on MCF-7 breast cancer cells.

• DOI: 10.1371/journal.pone.0084646
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Lubovac-Pilav Z;Borràs DM;Ponce E;Louie MC
• 通讯作者: Louie MC

Chronic cadmium exposure stimulates SDF-1 expression in an ERα dependent manner.

慢性镉暴露以ERα依赖性方式刺激SDF-1表达。

• DOI: 10.1371/journal.pone.0072639
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Ponce,Esmeralda;Aquino,NatalieB;Louie,MaggieC
• 通讯作者: Louie,MaggieC