Growth inhibition and increase of insulin receptors in antiestrogen-resistant T47DCO human breast cancer cells by progestins: implications for endocrine therapies.
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. However, it is not known whether progestins inhibit the growth of breast tumor cells directly and independently of estradiol. To study this, we have used T47DCO human breast cancer cells. The progesterone receptors in these cells do not require estrogen induction, and this permits study of pure progestin effects without interference by estradiol. We report here that, in the absence of estradiol, physiological concentrations of progestins directly inhibit proliferation of these cells. At the same time, progestins increase 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 suppresses cell growth approximately 50 to 60%. This is consistent with the concentrations that either partially (approximately 10%) or more extensively (greater than 60%) translocate cytoplasmic progesterone receptors. Even a brief 1-hr pulse of R5020 has long-term growth-inhibitory effects. Progesterone is also antiproliferative, but its effects are attenuated because, unlike R5020, it is rapidly metabolized in the medium. Other synthetic progestins also inhibit cell growth, but unrelated steroids (estradiol, androgens, glucocorticoids, 1,25-dihydroxyvitamin D3) are ineffective. While growth is suppressed by R5020, insulin receptors increase rapidly and then fall to a new, elevated steady state as the cells slowly begin to proliferate. Only progestins have this effect on insulin receptors. We conclude that the hormonal regulation of breast tumor cell growth is complex and includes progestins among the regulating factors. Furthermore, 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. We propose that, clinically, antiestrogens and progestins may have complementary uses in breast cancer treatment, and we outline two therapeutic strategies.
D019326:17-alpha-Hydroxyprogesterone; D000728:Androgens / Q000494:pharmacology; D001943:Breast Neoplasms / Q000473:pathology*; D002117:Calcitriol / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004273:DNA, Neoplasm / Q000032:analysis; D003907:Dexamethasone / Q000494:pharmacology; D004351:Drug Resistance; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D006908:Hydroxyprogesterones / Q000494:pharmacology*; D007700:Kinetics; D009649:Norpregnadienes / Q000494:pharmacology*; D011397:Promegestone / Q000494:pharmacology*; D011972:Receptor, Insulin / Q000187:drug effects / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism
D000728:Androgens; D004273:DNA, Neoplasm; D006908:Hydroxyprogesterones; D009649:Norpregnadienes; D011980:Receptors, Progesterone; D004958:Estradiol; D019326:17-alpha-Hydroxyprogesterone; D003907:Dexamethasone; D011397:Promegestone; D011972:Receptor, Insulin; D002117:Calcitriol; D006854:Hydrocortisone