2',3',4'-Trihydroxychalcone changes estrogen receptor α regulation of genes and breast cancer cell proliferation by a reprogramming mechanism.
2',3',4'-Trihydroxychalcone changes estrogen receptor α regulation of genes and breast cancer cell proliferation by a reprogramming mechanism.
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DOI：
10.1186/s10020-022-00470-z
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发表时间：
2022-04-25
影响因子：
5.7
通讯作者：
Leitman, Dale C.
中科院分区：
文献类型：
--
作者：
Herber, Candice B.;Yuan, Chaoshen;Chang, Anthony;Wang, Jen-Chywan;Cohen, Isaac;Leitman, Dale C.
关键词：
由于长期治疗的安全性问题，绝经期激素治疗（MHT）仅推荐5年用于治疗血管舒缩症状和外阴阴道萎缩。我们研究了2 ',3 ',4 ' -三羟基查尔酮（2 ',3 ',4 ' -THC）调节雌激素受体（ER）介导的反应的能力，以寻找可能预防长期MHT治疗不良反应的候选药物。转染实验、实时聚合酶链反应和微阵列技术被用于评估2 ',3 ',4 ' -THC对基因调控的影响。放射性配体结合研究用于确定2 ',3 ',4 ' -THC是否与ERα结合。采用生长曲线和流式细胞术检测MCF-7乳腺癌细胞的增殖情况。Western blots检测2 ',3 ',4 ' -THC是否改变E2活化MAPK通路和ERα的降解。染色质免疫沉淀法测定ERα与基因的结合。2 ',3 ',4 ' -THC/E2组合与ERα协同激活人U2OS骨肉瘤细胞的报告基因和内源性基因。微阵列鉴定了824个基因，我们称之为重编程基因，因为它们在u20s - erα细胞中不受调节，除非它们同时被2 ',3 ',4 ' -THC和E2处理。2 ',3 ',4 ' -THC通过阻止e2诱导的MAPK和c-MYC转录的激活来阻断MCF-7细胞的增殖。2 ',3 ',4 ' -THC的抗增殖机制不同于选择性雌激素受体调节剂（SERMs），因为在ERα样SERMs中，2 ',3 ',4 ' -THC不结合E2结合位点。我们的研究表明，2 ',3 ',4 ' -THC可能代表了一类新的ERα调节剂，不作为直接的激动剂或拮抗剂。我们认为2 ',3 ',4 ' -THC是一种重编程化合物，因为它改变了ERα对基因调控和细胞增殖的活性，而不与E2竞争ERα的结合。在MHT中的雌激素中加入重编程药物可能提供一种新的策略，通过重编程ERα来克服雌激素在MHT中的不良增殖作用，而不是通过阻断雌激素与ERα结合的拮抗剂机制。在线版本包含补充材料，下载地址为10.1186/s10020-022-00470-z。
Menopausal hormone therapy (MHT) is recommended for only five years to treat vasomotor symptoms and vulvovaginal atrophy because of safety concerns with long-term treatment. We investigated the ability of 2′,3′,4′-trihydroxychalcone (2′,3′,4′-THC) to modulate estrogen receptor (ER)-mediated responses in order to find drug candidates that could potentially prevent the adverse effects of long-term MHT treatment. Transfection assays, real time-polymerase chain reaction, and microarrays were used to evaluate the effects of 2′,3′,4′-THC on gene regulation. Radioligand binding studies were used to determine if 2′,3′,4′-THC binds to ERα. Cell proliferation was examined in MCF-7 breast cancer cells by using growth curves and flow cytometry. Western blots were used to determine if 2′,3′,4′-THC alters the E2 activation of the MAPK pathway and degradation of ERα. Chromatin immunoprecipitation was used to measure ERα binding to genes. The 2′,3′,4′-THC/E2 combination produced a synergistic activation with ERα on reporter and endogenous genes in human U2OS osteosarcoma cells. Microarrays identified 824 genes that we termed reprogrammed genes because they were not regulated in U2OS-ERα cells unless they were treated with 2′,3′,4′-THC and E2 at the same time. 2′,3′,4′-THC blocked the proliferation of MCF-7 cells by preventing the E2-induced activation of MAPK and c-MYC transcription. The antiproliferative mechanism of 2′,3′,4′-THC differs from selective estrogen receptor modulators (SERMs) because 2′,3′,4′-THC did not bind to the E2 binding site in ERα like SERMs. Our study suggests that 2′,3′,4′-THC may represent a new class of ERα modulators that do not act as a direct agonists or antagonists. We consider 2′,3′,4′-THC to be a reprogramming compound, since it alters the activity of ERα on gene regulation and cell proliferation without competing with E2 for binding to ERα. The addition of a reprogramming drug to estrogens in MHT may offer a new strategy to overcome the adverse proliferative effects of estrogen in MHT by reprogramming ERα as opposed to an antagonist mechanism that involves blocking the binding of estrogen to ERα. The online version contains supplementary material available at 10.1186/s10020-022-00470-z.
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影响因子：
39
作者：
Avis, Nancy E.;Crawford, Sybil L.;Greendale, Gail;Bromberger, Joyce T.;Everson-Rose, Susan A.;Gold, Ellen B.;Hess, Rachel;Joffe, Hadine;Kravitz, Howard M.;Tepper, Ping G.;Thurston, Rebecca C.
通讯作者：
Thurston, Rebecca C.
DOI：
10.1038/nrm.2016.122
发表时间：
2016-12
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Levin ER;Hammes SR
通讯作者：
Hammes SR
影响因子：
2.7
作者：
Komm, Barry S.;Mirkin, Sebastian;Jenkins, Simon N.
通讯作者：
Jenkins, Simon N.
终生风险和心血管疾病首发表现的性别差异：基于人群的前瞻性队列研究。
DOI：
10.1136/bmj.g5992
发表时间：
2014-11-17
期刊：
BMJ (Clinical research ed.)
影响因子：
--
作者：
Leening MJ;Ferket BS;Steyerberg EW;Kavousi M;Deckers JW;Nieboer D;Heeringa J;Portegies ML;Hofman A;Ikram MA;Hunink MG;Franco OH;Stricker BH;Witteman JC;Roos-Hesselink JW
通讯作者：
Roos-Hesselink JW
DOI：
10.1007/s10928-019-09626-7
发表时间：
2019-04-01
影响因子：
2.5
作者：
Benet, Leslie Z.;Bowman, Christine M.;Sodhi, Jasleen K.
通讯作者：
Sodhi, Jasleen K.