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Differential Effects of Estrogen and Antiestrogen on Transforming Growth Factor Gene Expression in Endometrial Adenocarcinoma Cells¹

Departments of Internal Medicine [L. J. M.], Physiology [Y. G., G. B., L. J. M.], and Biochemistry [L. C. M.], Faculty of Medicine, University of Manitoba, Winnipeg, Canada, R3E 0W3

While antiestrogens are useful agents in the treatment of breast cancer, the usefulness of these agents in the treatment of endometrial cancer remains controversial. There is some concern that the currently available antiestrogens may have partial agonist activity in uterine tissue. To better understand the mechanisms by which estrogens and antiestrogens modulate growth of endometrial adenocarcinoma cells, we have compared the effects of 17-ß estradiol and three antiestrogens, 4-hydroxytamoxifen (OH-TAM), ICI 164384, and LY 117018 on proliferation and transforming growth factor (TGF) mRNA accumulation in two human endometrial adenocarcinoma cell lines. In HEC-50 cells, neither estradiol nor antiestrogens had any effect on cell proliferation or TGF mRNA abundance under estrogen-depleted culture conditions [basal medium containing 1% twice charcoal-treated fetal bovine serum (ctFBS)] or in the presence of estrogen (basal medium containing 5% fetal bovine serum). At very high concentrations, both estradiol and OH-TAM caused a small decrease in HEC-50 cell proliferation in medium containing 5% serum. In contrast, the antiestrogens had different effects on Ishikawa cells, depending upon the culture conditions. In medium containing 5% fetal bovine serum, the antiestrogens inhibited cell proliferation and significantly decreased TGF- mRNA abundance and TGF- secretion. OH-TAM was more potent than the other antiestrogens. Under these culture conditions, estradiol had no effect on cell proliferation or TGF- mRNA levels but increased TGF- secretion. In medium supplemented with 1% ctFBS, estradiol increased cell proliferation and TGF- mRNA (2.72-fold, P < 0.005) and TGF- secretion (700 ± 156 versus 250 ± 23 pg/10⁶ cells/24 h, P < 0.05), whereas OH-TAM, which also stimulated cell proliferation, reduced TGF- mRNA abundance (P < 0.05) but had no significant effect on TGF- secretion. Under these conditions, ICI 164384 and LY 117018 had no effect on either cell proliferation or TGF- expression. Estradiol treatment decreased, whereas OH-TAM increased, epidermal growth factor receptors in Ishikawa cells. Both estradiol and the antiestrogens decreased TGF-ß, mRNA abundance when cells were grown in media containing 1% ctFBS. In summary, the response of human endometrial adenocarcinoma cells to estrogen and antiestrogens varied between cell lines and was dependent upon the culture conditions used. In addition, OH-TAM, unlike the other two antiestrogens tested, had growth-stimulating effects on Ishikawa cells.

¹ This work was supported by grants from the Manitoba Health Research Council, The Cancer Research Society, and the National Cancer Institute of Canada.

² Visiting Scientist sponsored by the Interamerican Development Bank/University of Sao Paulo Grant. Permanent address: Department of Pharmacology, Faculty of Medicine Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil.

³ To whom requests for reprints should be addressed, at University of Manitoba, Department of Internal Medicine and Physiology, Room 435 Basic Science Building, 770 Bannatyne Ave., Winnipeg R3E 0W3, Canada.

Received 10/ 8/91. Accepted 1/23/92.