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Enhanced formation of non-phenolic androgen metabolites with intrinsic oestrogen-like gene transactivation potency in human breast cancer cells: a distinctive metabolic pattern.
- Source :
-
The Journal of endocrinology [J Endocrinol] 2006 Sep; Vol. 190 (3), pp. 805-18. - Publication Year :
- 2006
-
Abstract
- Breast cancer is a sex steroid hormone-dependent malignant neoplasia. The role of oestradiol in this malignancy has been well documented; however, the involvement of androgens has remained controversial. To determine the role of non-phenolic androgen metabolites in human breast cancer, we studied the metabolism of [(14)C] testosterone and [(14)C] androstenedione in oestrogen-dependent MCF-7 cells and non-oestrogen-dependent MDA-MB 231 cells, at different substrate concentrations (1-10 muM) and time periods (30 min-48 h). Cultured non-oestrogen-dependent HeLa and yeast cells served as controls. Metabolites were identified and quantified by reverse isotope dilution. A distinctive pattern of androgen metabolism was identified in MCF-7 cells, being the 5alpha-androstane-3alpha,17beta-diol (3alpha,5alpha-diol) and its 3beta epimer (3beta,5alpha-diol), the major conversion products of testosterone (48.3%), with 5alpha-dihydrotestosterone as intermediary. The formation of 3alpha,5alpha-diol and 3beta,5alpha-diol (diols) was substrate concentration- and time-dependent, and abolished by finasteride. In contrast, very little of any diol formation was observed in MDA-MB 231, HeLa and yeast cell incubations. Additional enzyme gene expression studies revealed an overexpression of 5alpha-steroid reductase type-1 in MCF-7 cells, as compared with MDA-MB 231 cells. The oestrogen-like activities of diols were assessed in HeLa cells co-transfected with expression vectors for alpha or beta subtypes of the human oestrogen receptor (hER) genes and for an oestrogen-responsive reporter gene. The results show that 3beta, 5alpha-diol and to a lesser extent 3alpha,5alpha-diol bind with high relative affinity to hERalpha and hERbeta. Both diols induced hER-mediated reporter gene transactivation in a dose-response manner, similar to that induced by oestradiol, though with lower potency, an effect that was abolished by ICI-182 780. Furthermore, 3beta,5alpha-diol and to lesser extent 3alpha,5alpha-diol induced MCF-7 cell proliferation. The overall results demonstrated that MCF-7 cells exhibit enhanced expression and activity of androgen-metabolising enzymes, leading to rapid and large diol formation, and provide evidence that these androgen metabolites exert a potent oestrogen-agonistic effect, at genomic level, in oestrogen-dependent breast cancer cells. The data suggest that diols may act as in situ intracrine factors in breast cancer and that its formation can be pharmacologically inhibited.
- Subjects :
- Analysis of Variance
Androstane-3,17-diol pharmacology
Androstenedione metabolism
Breast Neoplasms enzymology
Carbon Isotopes
Cell Line, Tumor
Dose-Response Relationship, Drug
Estrogen Receptor alpha genetics
Estrogen Receptor alpha metabolism
Estrogen Receptor beta genetics
Estrogen Receptor beta metabolism
Female
Gene Expression Profiling
HeLa Cells
Humans
Isotope Labeling
Testosterone metabolism
Transfection methods
Androgens metabolism
Breast Neoplasms metabolism
Estrogens
Transcriptional Activation
Subjects
Details
- Language :
- English
- ISSN :
- 0022-0795
- Volume :
- 190
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- The Journal of endocrinology
- Publication Type :
- Academic Journal
- Accession number :
- 17003281
- Full Text :
- https://doi.org/10.1677/joe.1.06407