GROWTH-INHIBITION AND INCREASE OF INSULIN-RECEPTORS IN ANTIESTROGEN-RESISTANT T47DCO HUMAN-BREAST CANCER-CELLS BY PROGESTINS - IMPLICATIONS FOR ENDOCRINE THERAPIES

Abstract

There is renewed interest in the use of progestins to treat advanced breast cancer because results with these agents are comparable to those obtained with antiestrogens. It is not known whether progestins inhibit the growth of breast tumor cells directly and independently of estradiol. T47Dco human breast cancer cells were studied. The progesterone receptors in these cells do not require estrogen induction and this permits study of pure progestin effects without interference by estradiol. In the absence of estradiol, physiological concentrations of progestins directly inhibit proliferation of these cells. At the same time, progestins increased the levels of the receptors for insulin, a common cell mitogen. Ten days of treatment with 1 or 10 nM of the synthetic progestin R5020 [17,21-dimethyl-19-nor-4,9-pregnadiene-3,20-dione] suppressed cell growth .apprx. 50-60%. This was consistent with the concentrations that either partially (.apprx. 10%) or more extensively (> 60%) translocate cytoplasmic progesterone receptors. Even a brief 1-h pulse of R5020 had long-term growth-inhibitory effects. Progesterone was also antiproliferative, but its effects were attenuated because, unlike R5020, it was rapidly metabolized in the medium. Other synthetic progestins also inhibit cell growth, but unrelated steroids (estradiol, androgens, glucocorticoids, 1,25-dihydroxyvitamin D3) were ineffective. While growth was suppressed by R5020, insulin receptors increased rapidly and then fell to a new, elevated steady state as the cells slowly began to proliferate. Only progestins had this effect on insulin receptors. The hormonal regulation of breast tumor cell growth is complex and includes progestins among the regulating factors. Since T47Dco cells are antiestrogen-resistant and estrogen receptor-negative, the antiproliferative effects of progestins must be mediated through mechanisms that differ from the cytotoxic effects of antiestrogens. Clinically, antiestrogens and progestins may have complementary uses in breast cancer treatment. Two therapeutic strategies were outlined.