Comparison of possible carcinogenic estradiol metabolites: Effects on proliferation, apoptosis and metastasis of human breast cancer cells
Introduction
Estrogens are mainly responsible for the proliferation of human breast epithelial cells. A possible association between estrogens and breast carcinogenesis is given by the increased mitotic rate which may accelerate the possibility of genomic mutations and thus may influence breast cancer risk. In vivo, 17β-estradiol, the most potent human estrogen, is mainly metabolized by hydroxylation at the A- or the D-ring [1]. Evidence is accumulating that certain estradiol metabolites may play a more important role in enhancing breast cancer risk than their parent substance, 17β-estradiol [2]. In this context the 4-hydroxylated and 16a-hydroxylated estradiol metabolites are of special interest. In the present experimental work, we have directly compared the effects of the main estradiol metabolites on proliferation, apoptosis and markers of metastasis of human breast cancer cells.
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Material and methods
17β-Estradiol (E2), 2-hydroxyestradiol (2-OHE2), 4-hydroxyestradiol (4-OHE2) and 16a-hydroxyestrone (16-OHE1) were purchased from Steraloids, USA. The test substances were dissolved in ethanol and diluted with an ethanol/buffer mixture to the appropriate test concentrations.
MCF-7, a human estrogen-receptor positive breast cancer cell line, was used for the experiments. The cells were maintained in Dulbecco's modified Eagle's medium (DMEM) containing 5% (v/v) fetal calf serum supplemented with
Results
The results of the proliferation of MCF-7 cells are depicted in Fig. 1. E2 elicited a significant increase in cell number over the entire concentration range tested. The highest proliferation rate was induced at the concentrations 0.1 and 1 nM with about a 40% increase as compared to the control value. The metabolite 2-OHE2 did not show any significant increase over the concentration range. 4-OHE2 significantly increased cell proliferation at the concentrations of 1 and 10 nM with values of about
Discussion
Two main hypotheses are currently discussed concerning estradiol metabolites and breast carcinogenesis. The first one favours the idea that overproduction of 16a-hydroxyestrone as compared to 2-hydroxyestrone may be responsible for increased breast carcinogenesis. This metabolite has been shown to have a potent estrogenic activity by binding irreversibly to the estrogen-receptor [4]. Thus, 16-OHE1 may activate estrogen-receptor mediated oncogene expression and growth stimulation for a prolonged
References (25)
- et al.
The biology of apoptosis
Hum Pathol
(2001) - et al.
Regulation of Fas ligand expression in breast cancer cells by estrogen: functional differences between estradiol and tamoxifen
J Steroid Biochem Mol Biology
(2000) - et al.
Concentration of 16α-hydroxyestrone in human plasma as measured by a specific RIA
J Steroid Biochem
(1983) - et al.
Metabolism of endogenous estrogens
- et al.
Functional role of estrogen metabolism in target cells: review and perspectives
Carcinogenesis
(1998) - et al.
ATP tumor chemosensitivity assay
- et al.
Covalent binding of the endogenous estrogen 16α-hydroxyestrone to estradiol receptor in human breast cancer cells: characterization and intranuclear localization
Proc Natl Acad Sci USA
(1988) - et al.
Estradiol 16α-hydroxylation in the mouse correlates with tumor incidence and presence of murine mammary tumor virus: a possible model for the hormonal etiology of breast cancer in humans
Proc Natl Acad Sci USA
(1985) - et al.
In vitro biotransformation of estradiol by explant cultures of murine mammary tissues
Breast Cancer Res Treat
(1989) - et al.
Molecular mechanisms of estrogen carcinogenesis
Annu Rev Pharmacol Toxicol
(1996)
4-Hydroxylation of estrogens as marker of human mammary tumors
Proc Natl Acad Sci USA
Estrogens as endogenous genotoxic agents—DNA adducts and mutations
J Natl Cancer Inst Monogr
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