Understanding the Effects of Cadmium on Breast Cancer Cell Growth

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。乳腺癌是由乳腺的异常生长引起的，而乳腺的异常生长通常是由卵巢产生的雌性激素雌激素调节的。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。雌激素受体的存在和缺失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。激素依赖性乳腺癌通常采用激素消融治疗和/或抗雌激素治疗。然而，激素反应性乳腺癌经常发展成一种更具侵略性的表型，这种表型与激素无关。在许多病例中，雌激素受体仍然存在，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包括镉等重金属在内的内分泌干扰物。研究表明，镉可能增强内质网功能，促进乳腺癌的发生。镉被认为是一种环境污染物，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 et al. 2000, Martin et al. 2003）。这表明，美国乳腺癌发病率的增加可能与人类接触镉有关。我实验室的初步研究结果还表明，镉可以以激素不依赖的方式促进乳腺癌细胞的生长，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，除了经典的内质网途径外，镉可能激活另一种信号传导机制。镉如何调节这些“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。本研究旨在明确镉在乳腺癌细胞增殖中的作用，揭示镉调控内质网和非内质网靶基因表达的分子机制。本研究的目的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。本研究的结果不仅可以更好地理解镉等环境污染物如何促进乳腺癌，而且还可以为雌激素受体如何调节经典和非经典ER靶基因表达提供新的见解。此外，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，设计更有效的激素难治性乳腺癌治疗方法。

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.