The Proliferative Response to p27 Down-Regulation in Estrogen Plus Progestin Hormonal Therapy is Lost in Breast Tumors.
The Proliferative Response to p27 Down-Regulation in Estrogen Plus Progestin Hormonal Therapy is Lost in Breast Tumors.
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DOI：
10.1016/j.tranon.2018.02.011
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发表时间：
2018-04
影响因子：
5
通讯作者：
Haslam SZ
中科院分区：
文献类型：
--
作者：
Aupperlee MD;Kariagina A;Zaremba N;Basson MD;Schwartz RC;Haslam SZ
在接受雌激素（E）+孕酮激素替代疗法（HRT）的绝经后妇女中观察到增殖和乳腺癌风险增加。孕激素的作用是通过两种孕激素受体（PR）亚型，PRA和PRB介导的，具有独特的转录活性和功能。目前的研究探讨激素调节PR亚型在正常绝经后人类乳腺和孕激素增加增殖和乳腺癌风险的机制。分析绝经后和绝经前妇女的良性乳腺活检标本以及绝经后妇女的乳腺肿瘤活检标本，研究E和E+醋酸甲羟孕酮（MPA）对PRA和PRB表达的调节作用。在绝经后乳腺激素替代治疗，PRA和PRB的表达减少相比，绝经前乳腺。绝经后乳腺的E（n = 12）和E+MPA（n = 13）HRT与PRA和PRB表达增加，核细胞周期蛋白E表达增加，核p27表达减少（n = 16）相比，没有HRT。与单独使用E的HRT相比，使用E+MPA HRT时，核p27进一步降低，NF-κ B配体受体激活剂（RANKL）表达增加。在管腔型乳腺癌中，与E HRT（n = 6）相比，E+MPA HRT（n = 6）也与细胞周期抑制剂p27的核表达降低相关，但与增殖增加无关。这些结果表明，p27介导的孕激素诱导的增殖在正常人乳腺癌和这种增殖反应的调节E+MPA在乳腺肿瘤中丢失。
Increased proliferation and breast cancer risk has been observed in postmenopausal women receiving estrogen (E) + progestin hormone replacement therapy (HRT). Progestin action is mediated through two progesterone receptor (PR) isoforms, PRA and PRB, with unique transcriptional activity and function. The current study examines hormonal regulation of PR isoforms in the normal postmenopausal human breast and the mechanism by which progestins increase proliferation and breast cancer risk. Archival benign breast biopsies from postmenopausal and premenopausal women, and luminal breast tumor biopsies from postmenopausal women, were analyzed for regulation of PRA and PRB expression by E and E+medroxyprogesterone acetate (MPA). In the postmenopausal breast without HRT, PRA and PRB expression was decreased compared to the premenopausal breast. Both E (n = 12) and E+MPA (n = 13) HRT in the postmenopausal breast were associated with increased PRA and PRB expression, increased nuclear cyclin E expression, and decreased nuclear p27 expression compared to no HRT (n = 16). With E+MPA HRT, there was a further decrease in nuclear p27 and increased Receptor Activator of NF-kappa B Ligand (RANKL) expression compared to E-alone HRT. In luminal breast cancers, E+MPA HRT (n = 6) was also associated with decreased nuclear expression of the cell cycle inhibitor p27 compared to E HRT (n = 6), but was not associated with increased proliferation. These results suggest that p27 mediates progestin-induced proliferation in the normal human breast and that regulation of this proliferative response by E+MPA is lost in breast tumors.
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共轭性雌激素和乳腺癌的发病率和乳腺癌的死亡率以及子宫切除术后妇女：妇女健康计划的扩展随访随机性安慰剂对照试验。
DOI：
10.1016/s1470-2045(12)70075-x
发表时间：
2012-05
期刊：
The Lancet. Oncology
影响因子：
--
作者：
Anderson GL;Chlebowski RT;Aragaki AK;Kuller LH;Manson JE;Gass M;Bluhm E;Connelly S;Hubbell FA;Lane D;Martin L;Ockene J;Rohan T;Schenken R;Wactawski-Wende J
通讯作者：
Wactawski-Wende J
影响因子：
4.8
作者：
Aupperlee, MD;Smith, KT;Haslam, SZ
通讯作者：
Haslam, SZ
影响因子：
5.3
作者：
Gonzalez-Suarez, Eva;Branstetter, Daniel;Dougall, William C.
通讯作者：
Dougall, William C.
影响因子：
4.8
作者：
Graham, J. Dinny;Mote, Patricia A.;Clarke, Christine L.
通讯作者：
Clarke, Christine L.
DOI：
10.7326/0003-4819-130-4_part_1-199902160-00003
发表时间：
1999-02-16
影响因子：
39.2
作者：
Greendale, GA;Reboussin, BA;Barrett-Connor, E
通讯作者：
Barrett-Connor, E