Estrogen and estrogen plus progestin act directly on the mammary gland to increase proliferation in a postmenopausal mouse model

Hormone replacement therapy (HRT) with ovarian hormones is an important the rapeutic modality for postmenopausal women. However, a negative side effect ol HRT is an increased risk of breast cancer. Surgical induction of menopa use by ovariectomy (OVX) in mice is an experimental model that may provide insights into the effects of hormone replacement therapy on the human breas t. We have developed a mouse model of early and late postmenopausal states to investigate the effects of HRT on the normal mammary gland. The purpose of this study was to determine if HRT-induced proliferation was due to the direct action of the hormones on the mammary gland, or mediated systemicall y by hormones or growth factors produced elsewhere in the body. Estrogen (E ) or E plus the synthetic progestin, R5020, were implanted directly into th e mammary glands of early (1 week post OVX) and late (5 week post OVX) post menopausal mice instead of administration by injection. We report that resp onses of early and late post-menopausal mice to implanted hormones were the same as those observed previously with systemically administered hormones. Implanted E conferred an enhanced proliferative response in the late postm enopausal gland characterized morphologically by enlarged duct ends. E + R5 020 implants induced similar degrees of cell proliferation in both postmeno pausal states but the morphological responses differed. Ductal sidebranchin g was observed in early postmenopausal mice, whereas duct end enlargement w as observed in late postmenopausal mice. The differences in morphological r esponse to E + R5020 in 5 week post OVX were associated with an inability o f E to induce progesterone receptors (PR) in the late postmenopausal gland. The responses of the late postmenopausal glands to E and E + P were very s imilar to that observed previously in immature pubertal glands in ovary-int act mice. In pubertal mice, PR cannot be induced by E unless the mammary gl and is pre-treated with EGF-containing implants. Similarly, herein pre-trea tment of the late postmenopausal mammary gland with EGF-containing implants restored PR induction by E. Thus. EGF may determine the sensitivity of the mammary gland to E and E + P in late postmenopause and at puberty. (C) 200 1 Wiley-Liss, Inc.