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受到雌激素的调节，雌激素是卵巢产生的雌性激素。雌激素的活性由雌激素受体（ER）介导，雌激素受体反过来调节乳腺生长和发育所必需的基因的表达。ER的存在和缺乏是乳腺癌发展的关键预后标志。大多数乳腺癌最初发展为激素依赖性，这意味着雌激素的存在可以促进癌症的进展。激素依赖性乳腺癌通常用激素消融疗法和/或抗雌激素治疗来治疗。然而，激素反应性乳腺癌经常发展成一个更积极的表型，是激素依赖性。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。一个潜在的机制可能涉及内分泌干扰物，包括镉等重金属。研究表明，镉可增强雌激素受体功能，促进乳腺癌的发生。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，并可能促进肿瘤生长的小鼠。（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。我实验室的初步研究结果还表明，镉可以以非激素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cycD 1，c-myc和CTD）和非经典ER靶基因（“非ER”）靶基因（即cyclin E1，cdk 2和ACTR）。这表明，除了经典的ER途径，镉可能会激活一个替代的信号机制。镉如何调节这些“非ER”靶基因以及ER在这一替代途径中的作用尚不清楚。本文的工作旨在描述镉在乳腺癌细胞增殖中的作用，并绘制出镉在调节ER和“非ER”靶基因表达中的作用的分子机制。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更好地了解镉等环境污染物如何促进乳腺癌，还将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大的临床贡献，包括筛查重金属毒性，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.