Analysis of tumor environmental response and oncogenic pathway activation identifies distinct basal and luminal features in HER2-related breast tumor subtypes.
Analysis of tumor environmental response and oncogenic pathway activation identifies distinct basal and luminal features in HER2-related breast tumor subtypes.
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DOI：
10.1186/bcr2899
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发表时间：
2011-06-07
期刊：
影响因子：
--
通讯作者：
Chi JT
中科院分区：
文献类型：
--
作者：
Gatza ML;Kung HN;Blackwell KL;Dewhirst MW;Marks JR;Chi JT
乳腺癌异质性的发生是由于许多致癌途径以及许多非遗传因素的失调，包括肿瘤微环境应激，如缺氧，乳酸酸中毒和葡萄糖剥夺。尽管这些非遗传因素的重要性已得到公认，但尚不清楚如何将这些因素整合到癌症的遗传框架中，作为理解肿瘤异质性的下一个逻辑步骤。我们在这里报告了一系列的基因表达特征的发展，以衡量微环境压力的影响。在1,143例乳腺肿瘤中研究了缺氧、乳酸酸中毒、酸中毒和葡萄糖剥夺的通路活性，这些乳腺肿瘤根据其不同的致癌通路模式分为17个乳腺肿瘤亚组。由547个乳腺肿瘤组成的验证数据集也用于确认主要发现，并利用代表性乳腺癌细胞系验证计算机模拟结果和机制研究。通过对乳腺肿瘤微环境应激和致癌事件的整合途径分析，我们发现了这两种肿瘤异质性来源之间的许多已知和新的相关性。关注两个人表皮生长因子受体2（HER 2）相关亚组之间的差异，先前根据致癌途径活性的模式确定，我们确定这些亚组在肿瘤微环境特征方面不同，包括缺氧。我们进一步证明，这些亚组中的每一个具有与基底和腔乳腺肿瘤一致的特征，包括致癌信号传导途径的模式、亚型特异性基因的表达和调节缺氧反应的细胞机制。重要的是，我们还证明了缺氧相关基因表达和基底相关基因表达的相关模式在HER 2相关肿瘤中是一致的，无论我们是使用内在基因列表（ERBB 2+）还是基于HER 2 IHC状态分析肿瘤，都是基于我们的基于通路的分类方案的功能。我们的研究结果证实了一种细胞系特异性现象，其中基底样肿瘤、具有高缺氧的HER 2相关肿瘤以及正常基底上皮细胞与管腔型相比表达增加的HIF-1α mRNA水平，并且HIF-1α的沉默导致缺氧诱导基因的表达降低。本研究证明了由不同致癌途径活性定义的HER 2相关亚组中微环境条件的差异，并为这些亚组之间观察到的缺氧反应差异提供了机制解释。总的来说，这些数据证明了基于途径的分类策略作为整合遗传和非遗传因素以研究肿瘤异质性基础的框架的潜力。
Breast cancer heterogeneity occurs as a consequence of the dysregulation of numerous oncogenic pathways as well as many non-genetic factors, including tumor microenvironmental stresses such as hypoxia, lactic acidosis, and glucose deprivation. Although the importance of these non-genetic factors is well recognized, it is not clear how to integrate these factors within the genetic framework of cancer as the next logical step in understanding tumor heterogeneity. We report here the development of a series of gene expression signatures to measure the influences of microenvironmental stresses. The pathway activities of hypoxia, lactic acidosis, acidosis and glucose deprivation were investigated in a collection of 1,143 breast tumors, which have been separated into 17 breast tumor subgroups defined by their distinct patterns of oncogenic pathways. A validation dataset comprised of 547 breast tumors was also used to confirm the major findings, and representative breast cancer cell lines were utilized to validate in silico results and mechanistic studies. Through the integrative pathway analysis of microenvironmental stresses and oncogenic events in breast tumors, we identified many known and novel correlations between these two sources of tumor heterogeneity. Focusing on differences between two human epidermal growth factor receptor 2 (HER2)-related subgroups, previously identified based on patterns of oncogenic pathway activity, we determined that these subgroups differ with regards to tumor microenvironmental signatures, including hypoxia. We further demonstrate that each of these subgroups have features consistent with basal and luminal breast tumors including patterns of oncogenic signaling pathways, expression of subtype specific genes, and cellular mechanisms that regulate the hypoxia response. Importantly, we also demonstrate that the correlated pattern of hypoxia-related gene expression and basal-associated gene expression are consistent across HER2-related tumors whether we analyze the tumors as a function of our pathway-based classification scheme, using the intrinsic gene list (ERBB2+), or based on HER2 IHC status. Our results demonstrate a cell lineage-specific phenomenon in which basal-like tumors, HER2-related tumors with high hypoxia, as well as normal basal epithelial cells express increased mRNA levels of HIF-1α compared to luminal types and silencing of HIF-1α results in decreased expression of hypoxia-induced genes. This study demonstrates differences in microenvironmental conditions in HER2-related subgroups defined by distinct oncogenic pathway activities, and provides a mechanistic explanation for differences in the observed hypoxia response between these subgroups. Collectively, these data demonstrate the potential of a pathway-based classification strategy as a framework to integrate genetic and non-genetic factors to investigate the basis of tumor heterogeneity.
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DOI：
10.1016/s0360-3016(01)01630-3
发表时间：
2001-10-01
影响因子：
7
作者：
Brizel, DM;Schroeder, T;Mueller-Klieser, W
通讯作者：
Mueller-Klieser, W
DOI：
10.1073/pnas.0912708107
发表时间：
2010-04-13
影响因子：
11.1
作者：
Gatza, Michael L.;Lucas, Joseph E.;Nevins, Joseph R.
通讯作者：
Nevins, Joseph R.
影响因子：
64.5
作者：
Kouros-Mehr, Hosein;Slorach, Euan M.;Werb, Zena
通讯作者：
Werb, Zena
影响因子：
4.8
作者：
Blagosklonny, MV;An, WG;Neckers, L
通讯作者：
Neckers, L
影响因子：
4.5
作者：
Chen JL;Lucas JE;Schroeder T;Mori S;Wu J;Nevins J;Dewhirst M;West M;Chi JT
通讯作者：
Chi JT