Raafat A M, Li S, Bennett J M, Hofseth L J, Haslam S Z
Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
J Cell Physiol. 2001 Apr;187(1):81-9. doi: 10.1002/1097-4652(2001)9999:9999<::AID-JCP1056>3.0.CO;2-0.
Hormone replacement therapy (HRT) with ovarian hormones is an important therapeutic modality for postmenopausal women. However, a negative side effect of HRT is an increased risk of breast cancer. Surgical induction of menopause by ovariectomy (OVX) in mice is an experimental model that may provide insights into the effects of hormone replacement therapy on the human breast. 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 systemically by hormones or growth factors produced elsewhere in the body. Estrogen (E) or E plus the synthetic progestin, R5020, were implanted directly into the mammary glands of early (1 week post OVX) and late (5 week post OVX) postmenopausal mice instead of administration by injection. We report that responses of early and late postmenopausal 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 postmenopausal gland characterized morphologically by enlarged duct ends. E+R5020 implants induced similar degrees of cell proliferation in both postmenopausal states but the morphological responses differed. Ductal sidebranching was observed in early postmenopausal mice, whereas duct end enlargement was observed in late postmenopausal mice. The differences in morphological response to E+R5020 in 5 week post OVX were associated with an inability of 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 similar to that observed previously in immature pubertal glands in ovary-intact mice. In pubertal mice, PR cannot be induced by E unless the mammary gland is pre-treated with EGF-containing implants. Similarly, herein pre-treatment 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.
使用卵巢激素的激素替代疗法（HRT）是绝经后女性重要的治疗方式。然而，HRT的一个负面副作用是乳腺癌风险增加。通过对小鼠进行卵巢切除术（OVX）来手术诱导绝经是一种实验模型，可能有助于深入了解激素替代疗法对人类乳腺的影响。我们已建立了早期和晚期绝经后状态的小鼠模型，以研究HRT对正常乳腺的影响。本研究的目的是确定HRT诱导的增殖是由于激素对乳腺的直接作用，还是由体内其他部位产生的激素或生长因子介导的全身性作用。将雌激素（E）或E加合成孕激素R5020直接植入早期（OVX后1周）和晚期（OVX后5周）绝经后小鼠的乳腺中，而不是通过注射给药。我们报告，早期和晚期绝经后小鼠对植入激素的反应与先前观察到的全身给药激素的反应相同。植入的E在晚期绝经后腺体中引起增强的增殖反应，其形态学特征是导管末端增大。E+R5020植入物在两种绝经后状态下诱导相似程度的细胞增殖，但形态学反应不同。在早期绝经后小鼠中观察到导管侧支，而在晚期绝经后小鼠中观察到导管末端增大。OVX后5周对E+R5020的形态学反应差异与E在晚期绝经后腺体中无法诱导孕激素受体（PR）有关。晚期绝经后腺体对E和E+P的反应与先前在卵巢完整小鼠的未成熟青春期腺体中观察到的非常相似。在青春期小鼠中，除非用含表皮生长因子（EGF）的植入物对乳腺进行预处理，否则E不能诱导PR。同样，在此用含EGF的植入物对晚期绝经后乳腺进行预处理可恢复E诱导的PR。因此，EGF可能决定了晚期绝经后和青春期乳腺对E和E+P的敏感性。
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