The gene expression landscape of breast cancer is shaped by tumor protein p53 status and epithelial-mesenchymal transition.
The gene expression landscape of breast cancer is shaped by tumor protein p53 status and epithelial-mesenchymal transition.
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DOI：
10.1186/bcr3236
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发表时间：
2012-07-27
期刊：
影响因子：
--
通讯作者：
Ringnér M
中科院分区：
文献类型：
--
作者：
Fredlund E;Staaf J;Rantala JK;Kallioniemi O;Borg A;Ringnér M
来自临床癌症标本的基因表达数据提供了表征癌症特异性转录程序的机会。在这里，我们提出了一项分析，描绘了基于相关性的乳腺癌基因表达景观，确定了与乳腺癌特异性和一般肿瘤生物学密切相关的模块。从基于Pearson相关性构建的基因共表达网络中提取高度连接基因的模块，然后使用途径活性评分计算模块活性。利用KPL-4乳腺癌细胞系的siRNA细胞点微阵列系统和功能研究的基因表达数据，对模块的功能注释进行了实验验证。使用代表1608个乳腺癌样本的基因表达数据导出模块，并在代表971个独立乳腺癌样本和1231个其他癌症样本的数据集中进行验证。最初的共表达网络分析导致了8个严格调控的基因模块的表征。细胞周期基因被分为两个转录程序，使用siRNA筛选的实验验证显示这些程序在增殖过程中具有不同的功能作用。这两个程序的分离被发现作为肿瘤蛋白p53 （TP53）基因状态在腔内乳腺癌中的标志，只有在具有功能的p53（由TP53编码）的腔内肿瘤中，这两个程序才被分离。此外，一个包含成纤维细胞和基质相关基因的模块在成纤维细胞中高度表达，但在永生的人乳腺上皮细胞中，转化生长因子β 1 （tgf - β 1）和Snail等上皮-间充质过渡因子的过表达也会上调。引人注目的是，基质转录程序与低恶性肿瘤的管腔疾病和侵袭性淋巴结阳性疾病的基底样肿瘤有关。我们已经得到了一个强大的乳腺癌基因表达景观，反映了已知的亚型以及这些亚型的异质性。通过将这些模块应用于p53突变样本，我们揭示了非功能性p53在其他低增殖腔内乳腺癌中的生物学后果。此外，在基质模块的情况下，我们表明，一组共调节基因的生物学和临床解释是亚型依赖的。
Gene expression data derived from clinical cancer specimens provide an opportunity to characterize cancer-specific transcriptional programs. Here, we present an analysis delineating a correlation-based gene expression landscape of breast cancer that identifies modules with strong associations to breast cancer-specific and general tumor biology. Modules of highly connected genes were extracted from a gene co-expression network that was constructed based on Pearson correlation, and module activities were then calculated using a pathway activity score. Functional annotations of modules were experimentally validated with an siRNA cell spot microarray system using the KPL-4 breast cancer cell line, and by using gene expression data from functional studies. Modules were derived using gene expression data representing 1,608 breast cancer samples and validated in data sets representing 971 independent breast cancer samples as well as 1,231 samples from other cancer forms. The initial co-expression network analysis resulted in the characterization of eight tightly regulated gene modules. Cell cycle genes were divided into two transcriptional programs, and experimental validation using an siRNA screen showed different functional roles for these programs during proliferation. The division of the two programs was found to act as a marker for tumor protein p53 (TP53) gene status in luminal breast cancer, with the two programs being separated only in luminal tumors with functional p53 (encoded by TP53). Moreover, a module containing fibroblast and stroma-related genes was highly expressed in fibroblasts, but was also up-regulated by overexpression of epithelial-mesenchymal transition factors such as transforming growth factor beta 1 (TGF-beta1) and Snail in immortalized human mammary epithelial cells. Strikingly, the stroma transcriptional program related to less malignant tumors for luminal disease and aggressive lymph node positive disease among basal-like tumors. We have derived a robust gene expression landscape of breast cancer that reflects known subtypes as well as heterogeneity within these subtypes. By applying the modules to TP53-mutated samples we shed light on the biological consequences of non-functional p53 in otherwise low-proliferating luminal breast cancer. Furthermore, as in the case of the stroma module, we show that the biological and clinical interpretation of a set of co-regulated genes is subtype-dependent.
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影响因子：
8
作者：
Guedj, M.;Marisa, L.;de Reynies, A.;Orsetti, B.;Schiappa, R.;Bibeau, F.;MacGrogan, G.;Lerebours, F.;Finetti, P.;Longy, M.;Bertheau, P.;Bertrand, F.;Bonnet, F.;Martin, A. L.;Feugeas, J. P.;Bieche, I.;Lehmann-Che, J.;Lidereau, R.;Birnbaum, D.;Bertucci, F.;de The, H.;Theillet, C.
通讯作者：
Theillet, C.
影响因子：
11.2
作者：
Birkbak NJ;Eklund AC;Li Q;McClelland SE;Endesfelder D;Tan P;Tan IB;Richardson AL;Szallasi Z;Swanton C
通讯作者：
Swanton C
影响因子：
2.1
作者：
Boorjian, S;Ugras, S;Scherr, DS
通讯作者：
Scherr, DS
影响因子：
8
作者：
Farmer, P;Bonnefoi, H;Iggo, R
通讯作者：
Iggo, R
影响因子：
64.8
作者：
Curtis, Christina;Shah, Sohrab P.;Chin, Suet-Feung;Turashvili, Gulisa;Rueda, Oscar M.;Dunning, Mark J.;Speed, Doug;Lynch, Andy G.;Samarajiwa, Shamith;Yuan, Yinyin;Graef, Stefan;Ha, Gavin;Haffari, Gholamreza;Bashashati, Ali;Russell, Roslin;McKinney, Steven;Langerod, Anita;Green, Andrew;Provenzano, Elena;Wishart, Gordon;Pinder, Sarah;Watson, Peter;Markowetz, Florian;Murphy, Leigh;Ellis, Ian;Purushotham, Arnie;Borresen-Dale, Anne-Lise;Brenton, James D.;Tavare, Simon;Caldas, Carlos;Aparicio, Samuel
通讯作者：
Aparicio, Samuel