Inhibition of estrogen signaling activates the NRF2 pathway in breast cancer.
Inhibition of estrogen signaling activates the NRF2 pathway in breast cancer.
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DOI：
10.1007/s10549-010-1023-8
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发表时间：
2010-11
影响因子：
3.8
通讯作者：
Zhou, Qun
中科院分区：
文献类型：
--
作者：
Yao, Yuan;Brodie, Angela M. H.;Davidson, Nancy E.;Kensler, Thomas W.;Zhou, Qun
暴露于较高水平的雌激素产生遗传毒性代谢产物，可刺激乳腺肿瘤发生。诱导NF-E2相关因子2（NRF 2）依赖性解毒酶（例如，NAD（P）H-醌氧化还原酶1（NQO 1））被认为是对抗雌激素相关致癌作用的重要保护机制，因为它们有助于清除有毒雌激素。在这里，我们研究了雌激素受体（ER）信号对NRF 2依赖的基因转录的影响。在使用人NQO 1基因启动子的5-侧翼区的荧光素酶测定实验中，我们观察到ERα配体结合结构域（LBD）是雌激素依赖性乳腺癌细胞中雌激素抑制NQO 1启动子活性所必需的。染色质免疫沉淀（ChIP）分析显示，雌激素在NQO 1启动子处募集ERα和III类组蛋白脱乙酰酶SIRT 1，导致NQO 1转录抑制。雌激素拮抗剂紫草素抑制ERα表达可逆转雌激素对NQO 1表达的抑制作用。因此，进行化学预防研究以监测紫草素对DNA损伤和肿瘤生长的影响。紫草素处理MCF-7乳腺癌细胞抑制雌激素诱导的8-羟基-2-脱氧鸟苷（8-OHdG），DNA损伤的标志物。NQO 1缺陷促进雌激素依赖性肿瘤形成，紫草素以NQO 1依赖性方式抑制MCF-7异种移植物中雌激素依赖性肿瘤生长。这些结果表明，雌激素受体信号通路对NRF 2依赖性酶具有抑制作用。此外，紫草素逆转了雌激素对这一通路的抑制作用，可能有助于预防乳腺癌。
Exposure to higher levels of estrogen produces genotoxic metabolites that can stimulate mammary tumorigenesis. Induction of NF-E2-related factor 2 (NRF2)-dependent detoxifying enzymes (e.g., NAD(P)H-quinone oxidoreductase 1 (NQO1)) is considered an important mechanism of protection against estrogen-associated carcinogenesis because they would facilitate removal of toxic estrogens. Here, we studied the impact of estrogen-receptor (ER) signaling on NRF2-dependent gene transcription. In luciferase assay experiments using the 5-flanking region of the human NQO1 gene promoter, we observe that ERα ligand-binding domain (LBD) is required for estrogen inhibition of NQO1 promoter activity in estrogen-dependent breast cancer cells. Chromatin immunoprecipitation (ChIP) assay shows that estrogen recruits ERα and a class III histone deacetylase SIRT1 at the NQO1 promoter, leading to inhibition of NQO1 transcription. Inhibition of ERα expression by the antiestrogen shikonin reverses the inhibitory effect of estrogen on NQO1 expression. As a consequence, a chemoprevention study was undertaken to monitor the impact of shikonin on DNA lesions and tumor growth. Treatment of MCF-7 breast cancer cells with shikonin inhibits estrogen-induced 8-hydroxy-2-deoxyguanosine (8-OHdG), a marker of DNA damage. NQO1 deficiency promotes estrogen-dependent tumor formation, and shikonin inhibits estrogen-dependent tumor growth in an NQO1-dependent manner in MCF-7 xenografts. These results suggest that estrogen-receptor signaling pathway has an inhibitory effect on NRF2-dependent enzymes. Moreover, shikonin reverses the inhibitory effects of estrogen on this pathway and may contribute to breast cancer prevention.
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影响因子：
3.6
作者：
De Iuliis, Geoffry N.;Thomson, Laura K.;Aitken, R. John
通讯作者：
Aitken, R. John
影响因子：
6.4
作者：
Yang, Huanjie;Zhou, Ping;Huang, Hongbiao;Chen, Di;Ma, Ningfang;Cui, Qiuzhi Cindy;Shen, Shouxing;Dong, Weihua;Zhang, Xiaoyan;Lian, Wen;Wang, Xuejun;Dou, Q. Ping;Liu, Jinbao
通讯作者：
Liu, Jinbao
影响因子：
30.8
作者：
Fagerholm, Rainer;Hofstetter, Barbara;Nevanlinna, Heli
通讯作者：
Nevanlinna, Heli
影响因子：
8
作者：
Montano, M. M.;Chaplin, L. J.;Rogan, E.
通讯作者：
Rogan, E.
DOI：
10.1073/pnas.94.20.10937
发表时间：
1997-09-30
影响因子：
11.1
作者：
Cavalieri, EL;Stack, DE;Rogan, EG
通讯作者：
Rogan, EG