Estrogen-stimulated Growth Research Articles

256. Use of female sex steroid receptors as a molecular approach for post coital contraception

Progesterone antagonists (PAs) (antiprogestins) or progesterone receptor modulators (PRMs) form an interesting category of new hormonal agents in the treatment of breast cancer. In vitro, antiproliferative effects of different PAs are mainly observed in estrogen-stimulated growth of PR-positive tumor cell lines. Both progestin agonist/antagonist actions on mammary tumor cells are dependent on the type of cell line, culture medium and concentrations of the PAs used, and type of biologic response measured. In various experimental animal tumor models, different PAs showed a greater antitumor activity than tamoxifen or high-dose progestins. Most interestingly, combination treatment of different PAs (mifepristone, ORG 31710, onapristone) or PRMs with different antiestrogens (tamoxifen, droloxifen, ICI 164384) or with an aromatase inhibitor (atemestane) showed greater antitumor efficacy than treatment with each single type of drug alone. These additive antiproliferative effects were demonstrated in various experimental in vitro and in vivo models. In some studies, these effects were accompanied by additive effects on several cell biologic parameters. In pretreated postmenopausal patients with metastatic breast cancer, objective responses have been observed in 10–12%, and stable disease in 42–46% of the patients; in previously untreated patients objective response rates of 11 and 56% have been reported. The clinical development of onapristone was stopped because of liver toxicity. At the present time, apart from development of new pure potent PAs, clinical investigation of combined therapy of PAs with antiestrogens are urgently needed.

Rapid inactivation of ovalbumin messenger ribonucleic acid after acute withdrawal of estrogen.

Synthesis of ovalbumin mRNA is induced and maintained in the avian oviduct by estrogen. When estrogen is rapidly removed from circulation, there is a general involution of the oviduct and an unusually rapid decay of ovalbumin mRNA activity. The kinetics of ovalbumin mRNA decay were not first order; instead, the rate of degradation increased about 10-fold over a 20-hr period after removal of estrogen. These results are in contrast with first-order decay kinetics observed for ovalbumin mRNA in estrogen-stimulated chicks (t(1/2) = about 24 hr) and in cell-free extracts. The degradative response triggered by hormonal withdrawal becomes more rapid between 1 and 4 days of estrogen-stimulated growth. We conclude that in the process of inducing egg-white protein synthesis, estrogen produces a cellular environment in which the egg-white protein mRNAs are relatively stable; removal of estrogen initiates cellular catabolism in a manner that is not understood.