Differential recruitment of coregulator proteins steroid receptor coactivator-1 and silencing mediator for retinoid and thyroid receptors to the estrogen receptor-estrogen response element by β-estradiol and 4-hydroxytamoxifen in human breast cancer
Differential recruitment of coregulator proteins steroid receptor coactivator-1 and silencing mediator for retinoid and thyroid receptors to the estrogen receptor-estrogen response element by β-estradiol and 4-hydroxytamoxifen in human breast cancer
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DOI：
10.1210/jc.2003-031048
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发表时间：
2004-01-01
影响因子：
5.8
通讯作者：
Young, LS
中科院分区：
文献类型：
--
作者：
Fleming, FJ;Hill, ADK;Young, LS
雌激素受体(ER)- α和ER- β作为转录因子，两者都与核调节蛋白相互作用，增强或抑制转录。我们假设共调节因子在乳腺癌中表达，并且可能在雌激素和他莫昔芬存在时被er不同地招募。er - β在淋巴结阴性患者中表达频率更高（P < 0.05）。类固醇受体共激活因子-1 （SRC-1）的表达与淋巴结阳性（P < 0.05）和内分泌治疗耐药（P < 0.001）相关。利用免疫荧光法建立er - α、er - β和协同调节蛋白的空间共表达。在两种细胞系（MCF-7和T47D）和原发性乳腺癌细胞培养中，β -雌二醇上调er - β和协同调节蛋白的表达，并增加er - α / er - β与雌激素反应元件（ERE）的相互作用。4-羟基-他莫昔芬（4-OHT）增加了er - α和类视黄醛和甲状腺受体（SMRT）表达的沉默介质，增加了ER-ERE的结合。在ER- ERE复合体上鉴定出SRC-1和SMRT，并利用免疫沉淀法确定ER异构体与协同调节蛋白之间的相互作用。在-雌二醇存在的情况下，er - α和er - β优先结合SRC-1。相反，在4-OHT处理的细胞中，er - α和er - β结合的SMRT。在β -雌二醇和4-OHT存在的情况下，er - α和er - β对SRC-1和SMRT的差异募集可能是肿瘤对内分泌治疗反应的核心。
Estrogen receptor (ER)-alpha and ER-beta function as transcription factors, and both interact with nuclear regulatory proteins to enhance or inhibit transcription. We hypothesized that coregulators are expressed in breast cancer and may be differentially recruited by ERs in the presence of estrogen and tamoxifen. ER-beta was found to be expressed more frequently in node-negative patients (P < 0.05). Expression of steroid receptor coactivator-1 (SRC-1) was associated with nodal positivity ( P < 0.05) and resistance to endocrine treatment ( P < 0.001). The spatial coexpression of ER-alpha, ER-beta, and the coregulatory proteins was established using immunofluorescence. In both cell lines (MCF-7 and T47D) and in primary breast cancer cell cultures, beta-estradiol up-regulated ER-beta and coregulator protein expression and increased ER-alpha/ER-beta interaction with the estrogen response element (ERE). 4-Hydroxy- tamoxifen (4-OHT) increased ER-alpha and silencing mediator for retinoid and thyroid receptors ( SMRT) expression and increased ER-ERE binding. SRC-1 and SMRT were identified at the ER- ERE complex, and interactions between ER isoforms and coregulatory proteins were determined using immunoprecipitation. Both ER-alpha and ER-beta preferentially bound SRC-1 in the presence of beta-estradiol. Conversely, in cells treated with 4-OHT, ER-alpha and ER-beta bound SMRT. Differential recruitment of SRC-1 and SMRT by ER-alpha and ER-beta in the presence of beta-estradiol and 4-OHT may be central to the response of the tumor to endocrine treatment.