Effects of bazedoxifene acetate with and without conjugated equine estrogens on the breast of postmenopausal monkeys.
Effects of bazedoxifene acetate with and without conjugated equine estrogens on the breast of postmenopausal monkeys.
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DOI：
10.1097/gme.0b013e318252e46d
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发表时间：
2012-11
期刊：
影响因子：
--
通讯作者：
Clarkson TB
中科院分区：
文献类型：
--
作者：
Ethun KF;Wood CE;Register TC;Cline JM;Appt SE;Clarkson TB
由于担心雌激素和孕激素治疗会增加患乳腺癌的风险，人们对孕激素替代品的兴趣日益浓厚。本研究的主要目的是确定醋酸巴多昔芬 (BZA) 这种新型选择性雌激素受体调节剂 (SERM) 是否会拮抗乳腺中结合马雌激素 (CEE) 的增殖和转录作用。作为一项为期 20 个月的临床前试验的一部分，95 只切除卵巢的食蟹猴（Macaca fasciculis）被随机分配接受不治疗或接受 BZA（20 毫克/天）、CEE（0.45 毫克/天）或 BZA 和 CEE 联合治疗（女性每日等效剂量）。这里提供的数据包括治疗 6 个月后的乳房效果。终点包括组织形态计量学、组织病理学评估、基因微阵列测定、特定 ERα 活性标记物的 PCR 定量以及性类固醇受体和增殖标记物 Ki67 的免疫组织化学检测。与单独的 CEE 相比，BZA+CEE 和 BZA 导致终末导管中的总上皮密度、小叶增大和 Ki67 免疫标记显着减少（全部 P < 0.05）。在 CEE 中添加 BZA 可以拮抗 ERα 调节基因的表达，例如 GREB1 和 TFF1（两者 P < 0.01），而单独使用 BZA 对 ERα 介导的转录活性影响很小。 BZA 和 BZA+CEE 没有显着上调与细胞周期进展和增殖相关的基因。与对照和 CEE 相比，BZA 联合或不联合 CEE 也导致小叶和终末导管 ERα 免疫标记减少（全部 P < 0.0001）。这些发现表明，临床相关剂量的 BZA 是乳房中的雌激素拮抗剂，支持了与传统雌激素 + 孕激素疗法相比，CEE + BZA 可能会降低乳腺癌风险的观点。
Concerns about increased breast cancer risk with estrogen and progestin therapy have led to an increased interest in progestin alternatives. The main objective of this study was to determine if bazedoxifene acetate (BZA), a new selective estrogen receptor modulator (SERM), would antagonize the proliferative and transcriptional effects of conjugated equine estrogens (CEE) in the breast. As part of a 20 month preclinical trial, ninety-five ovariectomized cynomolgus macaques (Macaca fascicularis) were randomized to receive no treatment or treatment with BZA (20 mg/d), CEE (0.45 mg/d), or BZA and CEE in combination (women’s daily equivalent doses). Data presented here include breast effects following 6 months of treatment. Endpoints included histomorphometry, histopathologic evaluations, gene microarray assays, PCR quantification of specific ERα activity markers, and immunohistochemical detection of sex steroid receptors, and the proliferation marker Ki67. BZA+CEE and BZA resulted in significantly less total epithelial density, lobular enlargement, and Ki67 immunolabeling in the terminal ducts compared to CEE alone (P < 0.05 for all). The addition of BZA to CEE antagonized the expression of ERα-regulated genes such as GREB1 and TFF1 (P < 0.01 for both), while BZA alone had minimal effects on ERα-mediated transcriptional activity. BZA and BZA+CEE did not significantly up-regulate genes related to cell cycle progression and proliferation. BZA with and without CEE also resulted in less lobular and terminal duct ERα immunolabeling compared to control and CEE (P < 0.0001 for all). These findings demonstrate that BZA given at a clinically relevant dose is an estrogen antagonist in the breast, supporting the idea that CEE + BZA may provide a lower breast cancer risk profile compared to traditional estrogen + progestin therapies.
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DOI：
10.1097/gme.0b013e3181d76953
发表时间：
2010-09
期刊：
Menopause (New York, N.Y.)
影响因子：
--
作者：
Brunner RL;Aragaki A;Barnabei V;Cochrane BB;Gass M;Hendrix S;Lane D;Ockene J;Woods NF;Yasmeen S;Stefanick M
通讯作者：
Stefanick M
影响因子：
6.7
作者：
Archer, David E.;Lewis, Vivian;Pickar, James H.
通讯作者：
Pickar, James H.
影响因子：
3.8
作者：
Cline, JM;Soderqvist, G;von Schoultz, B
通讯作者：
von Schoultz, B
影响因子：
120.7
作者：
Chlebowski, RT;Hendrix, SL;McTiernan, A
通讯作者：
McTiernan, A
DOI：
10.1097/gme.0b013e3181a7fb1e
发表时间：
2009-11-01
影响因子：
2.7
作者：
Harvey, Jennifer A.;Holm, Mary K.;Helzner, Eileen
通讯作者：
Helzner, Eileen