BRCA1 transcriptionally regulates genes involved in breast tumorigenesis
BRCA1 transcriptionally regulates genes involved in breast tumorigenesis
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DOI：
10.1073/pnas.062181799
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发表时间：
2002-05-28
影响因子：
11.1
通讯作者：
King, MC
中科院分区：
文献类型：
--
作者：
Welcsh, PL;Lee, MK;King, MC
遗传性突变和组织特异性体细胞突变导致BRCA1功能丧失，导致乳腺癌和卵巢癌。几乎所有BRCA1胚系突变都涉及BRCT C末端转录激活结构域的截断或丢失，这表明转录调控是野生型基因的关键功能。该项目的目的是确定BRCA1在转录调控中的作用与其在肿瘤抑制中的作用之间是否存在联系。我们开发了一种细胞系(其中可以诱导BRCA1)，并使用微阵列分析来比较内源性BRCA1水平较低的上皮细胞和BRCA1诱导水平较高2-4倍的细胞的转录谱。在这些表达水平上，BRCA1不能诱导细胞凋亡。对6个配对实验进行的非定向聚类分析揭示了373个基因，这些基因的表达在BRCA1诱导下发生了显著且一致的变化。62个基因的表达发生了超过2倍的变化。BRCA1调控的与乳腺肿瘤发生相关的基因包括雌激素反应基因MYC和细胞周期蛋白D1，它们在许多乳腺肿瘤中过表达；细胞因子信号转导途径的关键组成部分STAT1和JAK1；细胞外基质蛋白LN 3A；DNA结合转录激活因子抑制因子ID4，它反过来负面调节BRCA1的表达；以及在乳腺肿瘤细胞中表达缺失的前激素stanniocalin。BRCA1与ID4和锡钙素在原发乳腺和卵巢肿瘤中的协同表达被证实。
Loss of function of BRCA1 caused by inherited mutation and tissue-specific somatic mutation leads to breast and ovarian cancer. Nearly all BRCA1 germ-line mutations involve truncation or loss of the C-terminal BRCT transcriptional activation domain, suggesting that transcriptional regulation is a critical function of the wild-type gene. The purpose of this project was to determine whether there is a link between the role of BRCA1 in transcriptional regulation and its role in tumor suppression. We developed a cell line (in which BRCA1 can be induced) and used microarray analysis to compare transcription profiles of epithelial cells with low endogenous levels of BRCA1 vs. transcription profiles of cells with 2-4-fold higher induced levels of expression of BRCA1. At these levels of expression, BRCA1 did not induce apoptosis. Undirected cluster analysis of six paired experiments revealed 373 genes, the expression of which was altered significantly and consistently by BRCA1 induction. Expression of 62 genes was altered more than 2-fold. BRCA1-regulated genes associated with breast tumorigenesis included the estrogen-responsive genes MYC and cyclin D1, which are overexpressed in many breast tumors; STAT1 and JAK1, key components of the cytokine signal transduction pathway; the extracellular matrix protein laminin 3A; ID4, an inhibitor of DNA-binding transcriptional activators, which in turn negatively regulates BRCA1 expression; and the prohormone stanniocalcin, expression of which is lost in breast tumor cells. Coordinated expression of BRCA1 with ID4 and with stanniocalcin was confirmed in primary breast and ovarian tumors.