analysis of tumor environmental response and oncogenic pathway activation identifies distinct basal and luminal features in her2-related breast tumor subtypes分析肿瘤环境响应和致癌途径激活识别不同的基底和腔的特性her2-related乳房肿瘤亚型.pdfVIP

Gatza et al. Breast Cancer Research 2011, 13:R62 /content/13/3/R62 RESEARCH ARTICLE Open Access Analysis of tumor environmental response and oncogenic pathway activation identifies distinct basal and luminal features in HER2-related breast tumor subtypes 1,2† 1,2,3† 4 5 6 Michael L Gatza , Hsiu-Ni Kung , Kimberly L Blackwell , Mark W Dewhirst , Jeffrey R Marks and Jen-Tsan Chi1,2* Abstract Introduction: 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. Methods: 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. Results: 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 d