Identification of estrogen receptor dimer selective ligands reveals growth-inhibitory effects on cells that co-express ERα and ERβ.
Identification of estrogen receptor dimer selective ligands reveals growth-inhibitory effects on cells that co-express ERα and ERβ.
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DOI：
10.1371/journal.pone.0030993
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Xu W
中科院分区：
文献类型：
--
作者：
Powell E;Shanle E;Brinkman A;Li J;Keles S;Wisinski KB;Huang W;Xu W
雌激素在乳腺和前列腺疾病的发展中起着至关重要的作用。雌激素的转录效应是由ER-α和ER-β两种雌激素受体介导的，这两种受体在调节细胞增殖中起着相反的作用：ER-α是增殖性的，而ER-β是抗增殖性的。ERβ在ERα阳性癌细胞中的外源性表达可抑制雌激素诱导的细胞增殖，减少体内移植瘤的生长，提示ERβ可能通过形成ERα异二聚体对抗ERα/β的促增殖作用。尽管生化和细胞学证据表明，在共表达这两种受体的细胞中形成了ERα/β异源二聚体，但ERα/β异源二聚体的生物学作用仍有待阐明。在这里，我们报告了两种植物雌激素，它们在特定浓度下选择性地激活ERα/β异二聚体，使用基于细胞的两步高通量小分子筛选来检测ER转录活性和ER二聚体的选择性。通过使用特定浓度的ERα/β异源二聚体选择性配体，我们证明了ERα/β异源二聚体在共表达两种ER异构体的乳腺和前列腺细胞中具有生长抑制作用。此外，使用自动定量分析(AUCA)检测ERα和ERβ在人乳腺组织微阵列中的核表达，我们证明ERα和ERβ在乳腺肿瘤的同一细胞中共同表达。ERα和ERβ在同一细胞中的共表达支持了在生理和病理条件下形成ERα/β异二聚体的可能性，进一步表明靶向ERα/β异二聚体可能是治疗同时表达ERα和ERβ的癌症的一种新的治疗方法。
Estrogens play essential roles in the progression of mammary and prostatic diseases. The transcriptional effects of estrogens are transduced by two estrogen receptors, ERα and ERβ, which elicit opposing roles in regulating proliferation: ERα is proliferative while ERβ is anti-proliferative. Exogenous expression of ERβ in ERα-positive cancer cell lines inhibits cell proliferation in response to estrogen and reduces xenografted tumor growth in vivo, suggesting that ERβ might oppose ERα's proliferative effects via formation of ERα/β heterodimers. Despite biochemical and cellular evidence of ERα/β heterodimer formation in cells co-expressing both receptors, the biological roles of the ERα/β heterodimer remain to be elucidated. Here we report the identification of two phytoestrogens that selectively activate ERα/β heterodimers at specific concentrations using a cell-based, two-step high throughput small molecule screen for ER transcriptional activity and ER dimer selectivity. Using ERα/β heterodimer-selective ligands at defined concentrations, we demonstrate that ERα/β heterodimers are growth inhibitory in breast and prostate cells which co-express the two ER isoforms. Furthermore, using Automated Quantitative Analysis (AQUA) to examine nuclear expression of ERα and ERβ in human breast tissue microarrays, we demonstrate that ERα and ERβ are co-expressed in the same cells in breast tumors. The co-expression of ERα and ERβ in the same cells supports the possibility of ERα/β heterodimer formation at physio- and pathological conditions, further suggesting that targeting ERα/β heterodimers might be a novel therapeutic approach to the treatment of cancers which co-express ERα and ERβ.
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影响因子：
4.4
作者：
Grober OM;Mutarelli M;Giurato G;Ravo M;Cicatiello L;De Filippo MR;Ferraro L;Nassa G;Papa MF;Paris O;Tarallo R;Luo S;Schroth GP;Benes V;Weisz A
通讯作者：
Weisz A
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4.8
作者：
Cowley, SM;Hoare, S;Parker, MG
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Parker, MG
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4.8
作者：
Chang, Edmund C.;Frasor, Jonna;Katzenellenbogen, Benita S.
通讯作者：
Katzenellenbogen, Benita S.
影响因子：
--
作者：
Lindberg, MK;Movérare, S;Ohlsson, C
通讯作者：
Ohlsson, C
影响因子：
6.1
作者：
Heinonen, SM;Wähälä, K;Adlercreutz, H
通讯作者：
Adlercreutz, H