PDF(Sci-hub)
Abstract：
The Women\'s Health Initiative studies reported that the menopausal hormone therapy (MHT) regimen containing conjugated equine estrogen (CEE) and medroxyprogesterone acetate increased, whereas CEE alone reduced breast cancer incidence. These observations suggest the possibility that CEE might exert unique actions on breast and also suggest the need to eliminate the progestogen from MHT regimens. A MHT regimen called a tissue selective estrogen complex (TSEC), containing CEE plus bazedoxifene (BZA), to avoid the need for a progestogen, was developed and FDA approved. Our study addressed two questions regarding this TSEC: (i) whether CEE exert effects on breast cancer which differ from those of estradiol (E2 ) and (ii) whether BZA antagonize the effects of E2 and CEE on breast cancer? Two rodent models (NMU and ACI) were used to compare the effect of CEE with E2 on mammary tumor formation, proliferation and apoptosis. In both the NMU and ACI models, E2 significantly increased tumor incidence and multiplicity whereas in striking contrast CEE did not, even though the estrogenic effects of CEE and E2 on uterine weight were identical. Mechanistically E2 blocked whereas CEE stimulated apoptosis (cleaved caspase-3) in ACI animals and only E2 stimulated proliferation (Ki67). BZA exerted highly potent anti-estrogenic effects on tumors by completely blocking palpable tumor formation. These data suggest that the CEE/BZA TSEC may be a safer, breast-antagonistic, MHT agent for women and might have potential to prevent breast cancer while relieving menopausal symptoms.
摘要：
妇女健康倡议研究报告说，更年期激素治疗（MHT）方案含有共轭马雌激素（CEE）和醋酸甲羟孕酮增加，而单独CEE降低乳腺癌发病率。这些观察结果表明，CEE可能对乳房发挥独特作用，并且还表明需要从MHT方案中消除孕激素。一种称为组织选择性雌激素复合物（TSEC）的MHT方案，含有CEE加巴多昔芬（BZA），为了避免需要孕激素，已开发并获得FDA批准。我们的研究解决了有关此TSEC的两个问题：（i）CEE是否对乳腺癌产生不同于雌二醇（E2）的作用，以及（ii）BZA是否拮抗E2和CEE对乳腺癌的作用？两种啮齿动物模型（NMU和ACI）用于比较CEE和E2对乳腺肿瘤形成的影响，增殖和凋亡。在NMU和ACI模型中，E2显着增加肿瘤的发病率和多重性，而相反，CEE没有，尽管CEE和E2对子宫重量的雌激素作用是相同的。在ACI动物中,E2在机制上阻断,而CEE刺激细胞凋亡(裂解的caspase-3),并且仅E2刺激增殖(Ki67)。BZA通过完全阻断可触及的肿瘤形成而对肿瘤发挥高度有效的抗雌激素作用。这些数据表明CEE/BZATSEC可能更安全，乳房拮抗，MHT剂适用于女性，可能有预防乳腺癌的潜力，同时缓解更年期症状。
