Cadmium, Metallothionein and Breast Cancer Progression

描述（由申请人提供）：申请人首次证明3类金属硫蛋白MT-3在人类乳腺癌的一个亚群中过表达，并且过表达与预后不良的早期乳腺癌相关。申请人还证明，正常人类乳房没有检测到MT-3 mRNA或蛋白质的表达。申请人假设MT-3的早期过表达通过apoMT的产生从包括p53在内的重要调控分子中分离Zn +2，这反过来使早期乳腺癌细胞成为生长缓慢、化疗耐药、遗传不稳定的细胞，注定要经历进展。提出了三个具体目标。首先是证明MT-3的过表达可以作为早期乳腺癌注定要经历肿瘤进展的预后指标。第二个目的是确定MT-3基因在正常乳腺上皮细胞中转录沉默但在人类乳腺癌亚群中转录活跃的观察结果背后的机制。这一目标将通过确定MT-3启动子、启动子元件和参与调节乳腺癌MT-3 mRNA表达的转录因子的区域来实现。最后一个目的是确定正常乳腺上皮细胞被迫过度表达MT-3基因的机制，表达丰富的MT-3 mRNA，但不表达MT-3蛋白。[目的]明确翻译和蛋白水解在乳腺上皮细胞MT-3 mRNA和蛋白表达中的作用。这项应用的长期目标是阐明MT-3基因调控在人类乳腺癌中发生改变的机制，并将这些知识应用于了解乳腺癌细胞的肿瘤生物学，并改善乳腺癌患者的诊断、预后和最终治疗。

DESCRIPTION (provided by applicant): The applicant is the first to demonstrate that class 3 metallothionein, MT-3, is over expressed in a subset of human breast cancers and that over expression is associated with early breast cancers having a poor outcome. The applicant has also shown that the normal human breast has no detectable expression of MT-3 mRNA or protein. The applicant hypothesizes that the early over expression of MT-3 sequesters Zn +2 from important regulatory molecules, including p53, through the generation of apoMT and that this in turn renders the early breast cancer cell as a slow growing, chemotherapeutic resistant, genetically unstable cell destined to undergo progression. Three specific aims are proposed. The first is to demonstrate that the over expression of MT-3 can be developed as a prognostic indicator of early breast cancers destined to undergo tumor progression. The second aim is to define the mechanism underlying the observation that the MT-3 gene is transcriptionally silent in normal breast epithelial cells but transcriptionally active in a sub-set of human breast cancers. This goal will be accomplished by identifying the regions of the MT-3 promoter, the promoter elements, and the transcription factors involved in regulating MT-3 mRNA expression in breast cancer. The last aim is to define the mechanism underlying the observation that normal breast epithelial cells forced to over express the MT-3 gene, express abundant MT-3 mRNA, but no MT-3 protein. [To define the role that translation and proteolysis have in the expression of MT-3 mRNA and protein in the breast epithelial cell.] The long-term goal of this application is to elucidate the mechanism/s underlying the alterations of MT-3 gene regulation that occur in human breast cancer and to apply this knowledge to understanding the tumor biology of the breast cancer cell and to improve diagnosis, prognosis and ultimately treatment for the patient with breast cancer.