Molecular basis for estrogen receptor alpha deficiency in BRCA1-linked breast cancer.
Molecular basis for estrogen receptor alpha deficiency in BRCA1-linked breast cancer.
复制标题
BRCA1连接乳腺癌中雌激素受体α缺乏症的分子基础。
DOI：
10.1093/jnci/djm207
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发表时间：
2007-11-21
期刊：
影响因子：
--
通讯作者：
Harkin DP
中科院分区：
文献类型：
--
作者：
Hosey AM;Gorski JJ;Murray MM;Quinn JE;Chung WY;Stewart GE;James CR;Farragher SM;Mulligan JM;Scott AN;Dervan PA;Johnston PG;Couch FJ;Daly PA;Kay E;McCann A;Mullan PB;Harkin DP
与大多数散发性肿瘤相比，BRCA1突变型乳腺肿瘤通常是雌激素受体- α (ERα)阴性。本研究的目的是为BRCA1突变肿瘤中观察到的ERα缺乏提供机制。使用乳腺癌疾病特异性微阵列，我们鉴定了BRCA1突变体和散发性石蜡包埋乳腺肿瘤之间的差异调控转录本。我们使用qPCR特异性地测量了这些肿瘤样本中ERα mRNA的表达。在人乳腺癌细胞系中，还评估了brca1依赖性方式对ERα反活化、mRNA和蛋白表达的调节。最后，我们研究了在存在和不存在功能性BRCA1的情况下，细胞增殖对抗雌激素治疗的反应。我们发现，在BRCA1缺陷肿瘤和乳腺癌细胞系中，当缺乏功能性BRCA1时，ERα mRNA的表达降低。我们证明转录因子Oct-1将BRCA1招募到ERα启动子，并且BRCA1和Oct-1都是ERα表达所必需的。我们还提供证据证明，乳腺癌细胞系对抗雌激素治疗的反应依赖于BRCA1的功能，这一作用与BRCA1调节ERα表达水平的能力直接相关。在这项研究中，我们确定了一种新的机制来解释BRCA1表达突变或畸变与ERα缺乏之间的联系。我们证明BRCA1可以通过直接调节ERα表达来改变乳腺癌细胞对抗雌激素治疗的反应。
BRCA1 mutant breast tumors, in contrast to most sporadic tumors are typically Estrogen Receptor-alpha (ERα) negative. The purpose of this study was to provide a mechanism for the observed ERα deficiency in BRCA1 mutant tumors. Using a Breast Cancer Disease Specific Microarray, we identified differentially regulated transcripts between BRCA1 mutant and sporadic paraffin-embedded breast tumors. Using qPCR we specifically measured ERα mRNA expression in these tumor samples. Regulation of ERα transactivation, mRNA and protein expression in a BRCA1-dependent manner was also assessed in human breast cancer cell lines. Finally, we investigated cellular proliferation in response to anti-estrogen treatment in the presence and absence of functional BRCA1. We show that ERα mRNA expression is reduced in the absence of functional BRCA1 in both BRCA1 deficient tumors and breast cancer cell lines. We demonstrate that the transcription factor Oct-1 recruits BRCA1 to the ERα promoter and that both BRCA1 and Oct-1 are required for ERα expression. We also provide evidence to demonstrate that the response of breast cancer cell lines to anti-estrogen treatment is dependent on functional BRCA1, an effect that is directly related to the ability of BRCA1 to modulate ERα expression levels. In this study we identify a novel mechanism to explain the link between mutation or aberration of BRCA1 expression and ERα deficiency. We demonstrate that BRCA1 can alter the response of breast cancer cells to anti-estrogen therapy by directly modulating ERα expression.
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DOI：
10.1073/pnas.011404098
发表时间：
2001-01-02
影响因子：
11.1
作者：
Li, C;Wong, WH
通讯作者：
Wong, WH
DOI：
10.1073/pnas.98.1.130
发表时间：
2001-01-02
影响因子：
11.1
作者：
Beger, C;Pierce, LN;Wong-Staal, F
通讯作者：
Wong-Staal, F
DOI：
10.1016/s0960-0760(97)00023-x
发表时间：
1997-06-01
影响因子：
4.1
作者：
Castles, CG;Oesterreich, S;Fuqua, SAW
通讯作者：
Fuqua, SAW
影响因子：
5.3
作者：
Baldassarre, G;Battista, S;Fusco, A
通讯作者：
Fusco, A
影响因子：
11.5
作者：
Foulkes, WD;Metcalfe, K;Narod, SA
通讯作者：
Narod, SA