Meta-analysis and gene set enrichment relative to er status reveal elevated activity of MYC and E2F in the "basal" breast cancer subgroup.
Meta-analysis and gene set enrichment relative to er status reveal elevated activity of MYC and E2F in the "basal" breast cancer subgroup.
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DOI：
10.1371/journal.pone.0004710
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Ormandy CJ
中科院分区：
文献类型：
--
作者：
Alles MC;Gardiner-Garden M;Nott DJ;Wang Y;Foekens JA;Sutherland RL;Musgrove EA;Ormandy CJ
缺乏雌激素受体（ER）的乳腺癌可以根据预后差、高级别、独特的组织病理学和独特的分子特征与其他乳腺癌区分开来。这些特征进一步区分了雌激素受体阴性（ER-）肿瘤亚型，但靶向治疗目前仅限于过表达ErbB 2受体的肿瘤。为了揭示未来疗法可能开发的途径，我们对来自五个大型微阵列数据集的与ER状态相关的基因表达进行了荟萃分析。计算了每个Affyellow HG-U133 A探针组与ER状态的相关性，并通过使用基因集富集分析（GSEA）检测生物学定义的基因集的富集来定义区分ER-肿瘤的途径。正如预期的那样，ER-肿瘤中ER的直接转录靶点的表达被抑制，但受雌激素间接调控的基因的表达增强。我们还观察到独立的MYC和E2 F驱动的转录程序的富集。我们使用雌激素和MYC作用的细胞模型来确定乳腺癌中雌激素和MYC转录活性之间的相互作用。我们发现ER−乳腺癌的基础亚组显示出强烈的MYC转录反应，重现了雌激素受体阳性（ER+）乳腺癌细胞中观察到的间接雌激素反应。MYC的转录活性增加是基底乳腺癌的一个特征，其中它在不存在ER的情况下模拟了大部分雌激素反应，这表明这些癌症实现雌激素非依赖性的机制，并为这种预后不良的乳腺癌亚组提供了潜在的治疗靶点。
Breast cancers lacking the estrogen receptor (ER) can be distinguished from other breast cancers on the basis of poor prognosis, high grade, distinctive histopathology and unique molecular signatures. These features further distinguish estrogen receptor negative (ER−) tumor subtypes, but targeted therapy is currently limited to tumors over-expressing the ErbB2 receptor. To uncover the pathways against which future therapies could be developed we undertook a meta-analysis of gene expression from five large microarray datasets relative to ER status. A measure of association with ER status was calculated for every Affymetrix HG-U133A probe set and the pathways that distinguished ER− tumors were defined by testing for enrichment of biologically defined gene sets using Gene Set Enrichment Analysis (GSEA). As expected, the expression of the direct transcriptional targets of the ER was muted in ER− tumors, but the expression of genes indirectly regulated by estrogen was enhanced. We also observed enrichment of independent MYC- and E2F-driven transcriptional programs. We used a cell model of estrogen and MYC action to define the interaction between estrogen and MYC transcriptional activity in breast cancer. We found that the basal subgroup of ER− breast cancer showed a strong MYC transcriptional response that reproduced the indirect estrogen response seen in estrogen receptor positive (ER+) breast cancer cells. Increased transcriptional activity of MYC is a characteristic of basal breast cancers where it mimics a large part of an estrogen response in the absence of the ER, suggesting a mechanism by which these cancers achieve estrogen-independence and providing a potential therapeutic target for this poor prognosis sub group of breast cancer.
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影响因子：
12.3
作者：
Lin CY;Ström A;Vega VB;Kong SL;Yeo AL;Thomsen JS;Chan WC;Doray B;Bangarusamy DK;Ramasamy A;Vergara LA;Tang S;Chong A;Bajic VB;Miller LD;Gustafsson JA;Liu ET
通讯作者：
Liu ET
影响因子：
3.7
作者：
Adem, C;Soderberg, CL;Jenkins, RB
通讯作者：
Jenkins, RB
影响因子：
16
作者：
Leone, G;Sears, R;Nevins, JR
通讯作者：
Nevins, JR
DOI：
10.1073/pnas.0504300102
发表时间：
2005-11-01
影响因子：
11.1
作者：
Black, EP;Hallstrom, T;Nevins, JR
通讯作者：
Nevins, JR
影响因子：
30.8
作者：
Carroll, Jason S.;Meyer, Clifford A.;Brown, Myles
通讯作者：
Brown, Myles