Genomic agonism and phenotypic antagonism between estrogen and progesterone receptors in breast cancer.
Genomic agonism and phenotypic antagonism between estrogen and progesterone receptors in breast cancer.
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DOI：
10.1126/sciadv.1501924
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发表时间：
2016-06
期刊：
影响因子：
13.6
通讯作者：
Greene GL
中科院分区：
文献类型：
--
作者：
Singhal H;Greene ME;Tarulli G;Zarnke AL;Bourgo RJ;Laine M;Chang YF;Ma S;Dembo AG;Raj GV;Hickey TE;Tilley WD;Greene GL
ER和PR的单独和协同作用突出了PR在ER+/PR+乳腺癌中的预后和治疗价值。孕激素受体（PR）在乳腺癌中的功能作用及其对雌激素信号传导的影响仍存在争议。在原发性ER+（雌激素受体阳性）/PR+人类肿瘤中，我们报告PR作为基因组激动剂和表型拮抗剂重新编程雌激素信号。单独地，雌激素和孕酮通过以相似的方向但在不同的水平调节共同靶基因的表达而作为基因组激动剂。类似地，单独地，雌激素蛋白也是雌激素作用的弱表型激动剂。然而，在这两种激素的存在下，白藜芦醇蛋白表现为表型雌激素拮抗剂。PR重塑核小体以非竞争性地将ER基因组结合重定向到富含BRCA 1结合基序和连接PR和ER/PR复合物的位点的远端增强子。当两种激素都存在时，雌激素调节雌激素作用，使得响应性转录组、细胞过程和ER/PR向基因组位点的募集与仅用PR观察到的那些相关，而不是仅用ER。尽管存在这种总体相关性，但通过双重治疗调节的转录组模式与单独治疗充分不同，使得预测并观察到致癌过程的拮抗作用。使用选择性PR调节剂/拮抗剂（SPRM）CDB 4124与他莫昔芬组合的组合疗法引起T47 D肿瘤异种移植物的70%细胞毒性肿瘤消退，而单独疗法抑制肿瘤生长而没有净消退。我们的研究结果表明，PR重定向ER染色质结合拮抗雌激素信号，SPRM可以增强抗雌激素的反应，这表明ER+/PR+乳腺癌中的ER和PR的共同靶向应进行探索。
Individual and concerted actions of ER and PR highlight the prognostic and therapeutic value of PR in ER+/PR+ breast cancers. The functional role of progesterone receptor (PR) and its impact on estrogen signaling in breast cancer remain controversial. In primary ER+ (estrogen receptor–positive)/PR+ human tumors, we report that PR reprograms estrogen signaling as a genomic agonist and a phenotypic antagonist. In isolation, estrogen and progestin act as genomic agonists by regulating the expression of common target genes in similar directions, but at different levels. Similarly, in isolation, progestin is also a weak phenotypic agonist of estrogen action. However, in the presence of both hormones, progestin behaves as a phenotypic estrogen antagonist. PR remodels nucleosomes to noncompetitively redirect ER genomic binding to distal enhancers enriched for BRCA1 binding motifs and sites that link PR and ER/PR complexes. When both hormones are present, progestin modulates estrogen action, such that responsive transcriptomes, cellular processes, and ER/PR recruitment to genomic sites correlate with those observed with PR alone, but not ER alone. Despite this overall correlation, the transcriptome patterns modulated by dual treatment are sufficiently different from individual treatments, such that antagonism of oncogenic processes is both predicted and observed. Combination therapies using the selective PR modulator/antagonist (SPRM) CDB4124 in combination with tamoxifen elicited 70% cytotoxic tumor regression of T47D tumor xenografts, whereas individual therapies inhibited tumor growth without net regression. Our findings demonstrate that PR redirects ER chromatin binding to antagonize estrogen signaling and that SPRMs can potentiate responses to antiestrogens, suggesting that cotargeting of ER and PR in ER+/PR+ breast cancers should be explored.