Understanding the Effects of Cadmium on Breast Cancer Cell Growth

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，而乳腺通常受到雌激素的调节，雌激素是由卵巢产生的女性荷尔蒙。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的存在和缺失是乳腺癌发生发展的一个关键预后指标。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。激素依赖型乳腺癌通常采用激素消融治疗和/或抗雌激素治疗。然而，激素敏感型乳腺癌经常发展成一种更具侵袭性的表型，这种表型不依赖激素。在许多情况下，ER仍然存在，但它在激素难治性乳腺肿瘤发生中的作用尚不清楚。一种潜在的机制可能涉及内分泌干扰物，包括重金属，如镉。研究表明，镉可能增强ER功能，促进乳腺癌的发生发展。镉是一种环境污染物，通过饮食或香烟烟雾进入人体。最近的研究表明，镉可以刺激雌激素受体(ER)的活性，并可能促进小鼠肿瘤的生长。(Stoica等人)2000年，Martin等人，2003年)。这表明，美国乳腺癌发病率的增加可能与人类接触镉有关。我的实验室的初步研究结果还表明，镉可以促进乳腺癌细胞的生长，并以激素非依赖性的方式促进乳腺癌细胞的生长，并同时促进经典的ER靶基因(即cycd1、c-myc和CTD)和非经典的ER靶基因(非ER靶基因)的靶基因(即细胞周期蛋白E1、CDK2和ACTR)。这表明，除了经典的内质网途径外，镉还可能激活另一种信号机制。镉如何调控这些“非内质网”靶基因，以及内质网在这一替代途径中的作用尚不清楚。本研究旨在研究镉在乳腺癌细胞增殖中的作用，并阐明镉调控ER和非ER靶基因表达的分子机制。本研究的目的是描述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将提供更好的了解环境污染物如镉如何促进乳腺癌的发生，也将为雌激素受体如何调控经典和非经典ER靶基因的表达提供新的见解。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，设计更有效的激素耐药乳腺癌的治疗方法。

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 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.