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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA098832-03
Application #
7214615
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Lively, Tracy (LUGO)
Project Start
2005-04-01
Project End
2009-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
3
Fiscal Year
2007
Total Cost
$261,423
Indirect Cost
Name
University of North Dakota
Department
Pathology
Type
Schools of Medicine
DUNS #
102280781
City
Grand Forks
State
ND
Country
United States
Zip Code
58202
Somji, Seema; Garrett, Scott H; Zhou, Xu Dong et al. (2010) Absence of Metallothionein 3 Expression in Breast Cancer is a Rare, But Favorable Marker of Outcome that is Under Epigenetic Control. Toxicol Environ Chem 92:1673-1695
Singh, Rajendra K; Albrecht, Amy L; Somji, Seema et al. (2008) Alterations in metal toxicity and metal-induced metallothionein gene expression elicited by growth medium calcium concentration. Cell Biol Toxicol 24:273-81
Albrecht, Amy L; Singh, Rajendra K; Somji, Seema et al. (2008) Basal and metal-induced expression of metallothionein isoform 1 and 2 genes in the RWPE-1 human prostate epithelial cell line. J Appl Toxicol 28:283-93
Albrecht, Amy L; Somji, Seema; Sens, Mary Ann et al. (2008) Zinc transporter mRNA expression in the RWPE-1 human prostate epithelial cell line. Biometals 21:405-16
Wang, Rongying; Sens, Donald A; Garrett, Scott et al. (2007) The resistance of metallothionein to proteolytic digestion: an LC-MS/MS analysis. Electrophoresis 28:2942-52
Zhou, Xu Dong; Sens, Mary Ann; Garrett, Scott H et al. (2006) Enhanced expression of metallothionein isoform 3 protein in tumor heterotransplants derived from As+3- and Cd+2-transformed human urothelial cells. Toxicol Sci 93:322-30
Gurel, Volkan; Sens, Donald A; Somji, Seema et al. (2005) Post-transcriptional regulation of metallothionein isoform 1 and 2 expression in the human breast and the MCF-10A cell line. Toxicol Sci 85:906-15