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 i s 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.
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