Understanding the Effects of Cadmium on Breast Cancer Cell Growth

了解镉对乳腺癌细胞生长的影响

• 批准号: 7659086
• 负责人: Maggie C Louie
• 金额: $ 5.31万
• 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 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7659086
• 关键词: Ablation; Accounting; Biological Sciences; Breast; Breast Cancer Cell; Cadmium; Cancer Cell Growth; Cathepsins; Cell Cycle; Cell Proliferation; Cessation of life; Clinical; Collaborations; Cultured Cells; Data; Development; Diet; Education; Endocrine Disruptors; Environmental Pollution; Estrogen Antagonists; Estrogen Receptor Modulators; Estrogen Receptors; Estrogens; Exposure to; Female; Gene Expression; Gene Targeting; Genes; Growth; Growth and Development function; Heavy Metals; Hormone Responsive; Hormones; Incidence; Institution; Malignant Neoplasms; Mammary gland; Maps; Mediating; Modeling; Molecular; Mus; NCOA3 gene; Neoplasms; Ovary; Pathway interactions; Phase; Phenotype; Prognostic Marker; Refractory; Research; Research Personnel; Research Project Grants; Research Proposals; Research Training; Role; Screening procedure; Signal Transduction; Skin Cancer; Social Interaction; Students; Techniques; United States; United States National Institutes of Health; Western World; Woman; Work; base; bcl-1 Genes; c-myc Genes; carcinogenesis; career; cigarette smoking; design; experience; exposed human population; human CCNE1 protein; insight; malignant breast neoplasm; metal poisoning; receptor function; therapeutic target; 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 normally modulated by estrogen, the female hormone produced by the ovaries. 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 and 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. Hormone dependent breast cancers are typically treated with hormone ablation therapy and/or antiestrogen treatment. However, hormone responsive breast cancer frequently develops into a more aggressive phenotype that is hormone independent. In many cases, the ER is still present, but its role in hormone refractory breast tumorigenesis is unclear. A potential mechanism may involve endocrine disruptors including heavy metals such as cadmium. Studies have suggested that cadmium may enhance the ER function and promote the development of breast cancer. Cadmium is as an environmental contaminant that enters the body through diet or cigarette smoke. Recent studies have suggested that cadmium can stimulate estrogen receptor (ER) activity and may promote neoplastic growth in mice. (Stoica et al. 2000, Martin et al., 2003). This suggests that increased incidences of breast cancer in the US may be associated with human exposure to cadmium. My lab's preliminary findings also suggest that cadmium can enhance breast cancer cell growth in a hormone independent manner and promote both classical ER target genes (i.e. cycD1, c-myc and CTD) and non classical ER target genes ("non-ER") target genes (i.e. cyclin E1, cdk2 and ACTR). This suggests that in addition to the classical ER pathway, cadmium may activate an alternate signaling mechanism. How cadmium regulates these "non-ER" target genes and the role of ER in this alternate pathway are unclear. The work proposed here is aimed at characterizing the role of cadmium in breast cancer cell proliferation and map out the molecular mechanism of cadmium's role in regulating the expression of both ER and "non ER" target gene expression. The objectives of this study are to characterize the role of cadmium in breast carcinogenesis and dissect the molecular mechanism of its action. Results from this study will not only provide a better understanding of how environmental contaminants such as cadmium can promote breast cancer, but also offer new insights to how the estrogen receptor can regulate both classical and non-classical ER target gene expression. 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, designing more effective therapeutics for hormone- refractory breast cancer.

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，乳腺通常受雌激素的调节，雌激素是卵巢产生的雌激素。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的存在和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。依赖于激素的乳腺癌通常接受激素消融疗法和/或抗雌激素治疗治疗。然而，激素反应型乳腺癌经常发展成一种更具侵略性的表型，该表型独立于激素。在许多情况下，ER仍然存在，但其在激素难治性乳腺肿瘤发生中的作用尚不清楚。潜在的机制可能涉及内分泌干扰物，包括重金属，例如镉。研究表明，镉可以增强ER功能并促进乳腺癌的发展。镉是通过饮食或香烟烟进入身体的环境污染物。最近的研究表明，镉可以刺激雌激素受体（ER）活性，并可能促进小鼠的肿瘤生长。 （Stoica等，2000； Martin等，2003）。这表明，美国乳腺癌发生率的增加可能与人类接触镉有关。我的实验室的初步发现还表明，镉可以独立于激素的方式增强乳腺癌细胞的生长，并促进经典ER靶基因（即Cycd1，c-Myc和CTD）和非经典ER靶基因（“非ER”）靶基因（即Cyclin E1，CDK2和ACTR）。这表明，除了经典的ER途径外，镉还可以激活替代信号传导机制。镉如何调节这些“非ER”靶基因以及ER在此替代途径中的作用尚不清楚。此处提出的工作旨在表征镉在乳腺癌细胞增殖中的作用，并绘制镉在调节ER和“非ER”靶基因表达的表达中作用的分子机制。这项研究的目标是表征镉在乳腺癌发生中的作用，并剖析其作用的分子机制。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如何促进乳腺癌，而且还为雌激素受体如何调节经典和非经典ER靶基因表达提供了新的见解。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，确定与重金属相关的乳腺癌病例，为激素难治性乳腺癌设计更有效的治疗剂。