Aromatase Overexpression and Breast Cancer Development
Abstract
Estrogen can be metabolized to hydroxylated catechol estrogen, a genotoxic metabolite of estrogen, which causes DNA damage and tumors in animal models. In situ synthesis of estrogen in the breast through aromatase results in high tissue estrogen concentrations. We hypothesized that overexpression of aromatase in breast tissue increases tissue estradiol concentrations and consequent genotoxic metabolites, and eventually causes breast cancer. To test our hypothesis, we stably expressed aromatase cDNA in MCF-10A cells, a benign breast epithelial cell line. We have demonstrated that MCF-10A(arom) cells expressed functional aromatase. We demonstrated that MCF-10A(arom) cells expressed functional aromatase using tritiated water release assay and products isolation by thin layer chromatography. MCF-10A(arom) cells, incubated for 3 months with aromatase substrate, androstenedione, formed colonies in soft agar indicating the overexpression of aromatase induces cellular transformation. MCF-10A(arom) cells have all enzymes required to convert estrogen to catechoestrogens and quinine. Overexpression of aromatase enhanced production of genotoxic metabolites, which could be blocked by aromatase inhibitor, letrozole. We finished the long-term in vivo study. MCF-10A(arom) cells did not form tumors in nude mice.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2004
- Accession Number
- ADA435768
Entities
People
- Eleanor Rogan
- Ercole Cavalieri
- Jiping Wang
- Jose Russo
- Sandra Fernandez
- Sandra Gunselman
- Wei Yue
- Yuebai Li
Organizations
- University of Virginia