Estrogen-Induced Depurination of DNA: A Novel Target for Breast Cancer Prevention
Abstract
The BCCOE investigators made much progress in this second year. We demonstrated that the tumors induced in the ACI rat mammary gland regress when the implanted estradiol is removed. We showed that estrogen metabolites and glutathione conjugates in human nipple aspirates can be analyzed by ultra-performance liquid chromatograph/tandem mass spectrometry. Treatment of MCF-lOF cells (ER negative) with estradiol or 4-hydroxyestradiol leads to their transformation, which encompases loss of heterozygosity in chromosome 13q12.3 and mutations in the TP53 tumor suppressor gene in chromosome 17pl3.l. These changes occur even with the antiestrogen ICI1182780 present. We demonstrated that mutations are induced in a reporter gene in Big Blue rat mammary tissue by implantation with estradiol plus 4-hydroxyestradiol. We demonstrated that ovariectomized ERKO/Wnt-l mice implanted with estradiol develop mammary tumors, even when the mice are also treated with the pure antiestrogen fulvestrant. We have characterized MCF-lOF cell transformation at the combined levels of the complete genome and individual genes. We have analyzed estrogen metabolites, conjugates and depurinating DNA adducts in human nipple aspirates, MCF-10F cells and ERKO/Wnt-l mouse mammary tissue. Development of a web-based model reference tool has progressed. Overall, we made great progress in defining the role of estrogen metabolism in the etiology of breast cancer and identifying potential biomarkers of susceptibility.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2005
- Accession Number
- ADA437181
Entities
People
- Ercole L. Cavalieri
Organizations
- University of Nebraska Medical Center