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 (MCF-10A(exp arom)). We demonstrated that MCF-10A(exp arom) cells expressed functional aromatase using tritiated water release assay and products isolation by thin layer chromatography. MCF-10A(exp 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(exp 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. MCF- 10A(exp arom) cells did not form palpable tumor in nude mice suggesting that multiple factors are required for breast cancer initiation.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2004
- Accession Number
- ADA430376
Entities
People
- Ercole Cavalieri
- Jiping Wang
- Sandra Gunselman
- Wei Yue
- Yuebai Li
Organizations
- University of Virginia