Direct action of 17 beta-estradiol on mouse mammary ducts analyzed by sustained release implants and steroid autoradiography.

17 beta-Estradiol is a recognized mammary mitogen, but uncertainty exists as to whether its normal action is mediated exclusively through the pituitary or whether in addition direct effects of estradiol on mammary tissue may play a role in mammary growth and development. To further investigate the action of estradiol on the developing mammary ductal system of young mice, implants of biocompatible ethylene vinyl acetate copolymer, which deliver small amounts of steroid locally to the target tissue, were implanted into the mammary glands of castrated females in which the ductal system was static and end buds had regressed. Within 3 days end buds appeared in the vicinity of the implants but not elsewhere in the gland and not in other glands of the animal, indicating direct stimulation. The new end buds were histologically normal, displaying a visible cap (stem) cell layer with high levels of DNA synthesis. The antiestrogen keoxifene, which competes with estrogen for its receptors, inhibited end bud formation in the estradiol-implanted gland but failed to inhibit growth when implanted into the glands of intact, 5-week-old females. Time course and dose-response studies of estradiol stimulation were carried out in ovariectomized animals and were consistent with a direct action for estrogen. Steroid autoradiography revealed estrogen receptors in the lumenal cells of the end bud, in ductal epithelium, and in stroma adjacent to ducts, but none was detected in the rapidly proliferating cap cells. We conclude that estrogen, perhaps acting on nonepithelial target cells and probably in conjunction with extramammary factors, directly stimulates mammary ductal growth.