Induction and inhibition of estradiol hydroxylase activities in MCF-7 human breast cancer cells in culture.
The effects of estradiol, progesterone, and tamoxifen on the activity of estradiol 2- and 16 alpha-hydroxylases were studied in human breast cancer cell cultures using a radiometric assay. After 5 days' exposure to these compounds, incubations in the presence of either [2-3H]estradiol or [16 alpha-3H]estradiol as substrate were carried out. In MCF-7 cells, estradiol (10(-8) M), progesterone (10(-6) M) and tamoxifen (10(-6) M) significantly increased 16 alpha-hydroxylase activity (estradiol; 21% progesterone 10% to 32%; tamoxifen 21% to 31%; P less than 0.01). Synergistic effects were observed when the cells were successively exposed to tamoxifen and progesterone. Simultaneous treatment with tamoxifen plus estradiol or estradiol plus progesterone showed no change from estradiol alone. On the other hand, although estradiol had no direct effects on 2-hydroxylase activity, tamoxifen decreased this enzymatic activity significantly at 10(-6) M (23% to 37%). Progesterone acted synergistically to further decrease this reaction. Treatment with only progesterone caused an increase in 2-hydroxylation. In contrast, a subline of MCF-7 cells with low estrogen receptor levels showed only minimal enzyme-hormone responses. Likewise, treatment of the estrogen receptor-negative MDA-MB-231 human breast cancer cell line with these compounds showed no effects on either 2- or 16 alpha-hydroxylase activity. In the progesterone receptor-rich T47D cell line, estradiol decreased both activities while progesterone increased both.(ABSTRACT TRUNCATED AT 250 WORDS)
Niwa
T
T
Laboratory of Biochemical Endocrinology, Rockefeller University, New York, New York.
Bradlow
H L
HL
Fishman
J
J
Swaneck
G E
GE
D001189:Aryl Hydrocarbon Hydroxylases; D001943:Breast Neoplasms / Q000201:enzymology*; D019363:Cytochrome P-450 CYP1A1; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D004790:Enzyme Induction; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D006801:Humans; D011374:Progesterone / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D065607:Cytochrome P-450 Enzyme Inhibitors; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013629:Tamoxifen; D011374:Progesterone; D004958:Estradiol; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D039181:Steroid 16-alpha-Hydroxylase; C020120:estrogen 2-hydroxylase