Mechanism of Action of Antiestrogens in Breast Cancer and Uterine Cells (Estrogen Receptor)
Sheen, Yhun Yhong
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https://hdl.handle.net/2142/71446
Description
Title
Mechanism of Action of Antiestrogens in Breast Cancer and Uterine Cells (Estrogen Receptor)
Author(s)
Sheen, Yhun Yhong
Issue Date
1986
Department of Study
Physiology and Biophysics
Discipline
Physiology
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Biology, Animal Physiology
Abstract
The actions of antiestrogen (AE) on growth and protein synthesis were studied in human breast cancer cells and rat uterus. Antiestrogens bind with high affinity to the estrogen receptor (ER) and to additional microsomal binding sites to which estrogens do not bind called antiestrogen binding sites (AEBS). Studies with the triphenylethylene AE, H1285, and with t-Butylphenoxyethyl Diethylamine (BPEA) suggest that AE actions on growth and protein synthesis are mediated via the ER and not via the AEBS. H1285 has an affinity for ER (Kd 0.23 nM) comparable to that of estradiol, while H1285 was 30- to 100-fold more potent inhibitor of MCF-7 cell proliferation than was tamoxifen. H1285 evoked very minimal increases in cellular progesterone receptor levels, and no increase in plasminogen activator activity, and it suppressed plasminogen activator activity stimulated by estradiol. BPEA, which has an affinity for AEBS 6% that of tamoxifen and an affinity for ER less than 0.0003% that of estradiol, had no effect (at 10('-11) to 10('-6) M) on growth of MCF-7 cells and no effect on inhibition of the growth of MCF-7 cells by different concentrations of the AE tamoxifen. In addition, BPEA exhibited no uterotropic or antiuterotropic activity in immature rats and had no influence on the agonistic or antagonistic activity of varying concentrations of tamoxifen on uterine weight. Therefore, the occupancy of AEBS, at least by BPEA, does not modulate growth of the uterus or breast cancer cells. Antiestrogens were found to decrease the production of several estrogen-stimulated secreted glycoproteins of M(,r) 32,000, M(,r) 160,000, and M(,r) 52,000 from MCF-7 cells and also to stimulate production of a specific secreted glycoprotein of M(,r) 37,000 that is estrogen-inhibited. These proteins may be useful in studying the actions of estrogen and antiestrogen and may serve as useful markers for predicting the hormonal responsiveness of breast cancer in vivo.
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