Shan Liang, Yu Minshu, Snyderwine Elizabeth G
Chemical Carcinogenesis Section, Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892-4262, USA.
Carcinogenesis. 2005 Feb;26(2):503-9. doi: 10.1093/carcin/bgh330. Epub 2004 Nov 4.
Exposure to carcinogens through diet, the atmosphere and other means is generally regarded as influencing human cancer risk, but the impact of specific environmental carcinogens on human breast cancer incidence is still unknown. We examined whether distinct chemical carcinogens induce a unique transcriptional profile in mammary gland cancer that is characteristic of the etiologic agent. Rat mammary gland cancers (n = 34) were generated by various carcinogens, including the food-derived heterocyclic amines 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, 7,12-dimethylbenz[a]anthracene, N-nitrosomethylurea and 4-aminobiphenyl. The histopathology of the carcinomas was graded using a modified Scarff-Bloom-Richardson scheme and the gene expression profiles in the carcinomas were evaluated on a 10K cDNA microarray. Unsupervised hierarchical clustering analysis revealed two major clusters of carcinomas irrespective of the carcinogenic agent that distinguished two groups with different histopathological parameters (degree of differentiation, nuclear grade, mitotic activity, epithelial cell growth pattern and necrosis). Using class comparison analysis and hierarchical clustering of all carcinomas irrespective of histopathology, gene expression profiles were further shown to be statistically differentially expressed according to the carcinogenic agent. These findings indicate that the transcriptional program in carcinomas is unique to the etiologic agent and can be observed among a diverse set of carcinogens despite variations in carcinoma histopathology. The ability to use microarray analysis to discern an etiology-specific profile among a pathologically heterogeneous group of breast carcinomas may ultimately be valuable in determining the role of environmental chemical carcinogens in human breast cancer risk.
通过饮食、大气及其他途径接触致癌物通常被认为会影响人类患癌风险，但特定环境致癌物对人类乳腺癌发病率的影响仍不明确。我们研究了不同化学致癌物是否会在乳腺癌中诱导出具有病因学特征的独特转录谱。通过多种致癌物诱发大鼠乳腺癌（n = 34），这些致癌物包括食物来源的杂环胺2-氨基-1-甲基-6-苯基咪唑[4,5-b]吡啶和2-氨基-3,8-二甲基咪唑[4,5-f]喹喔啉、7,12-二甲基苯并[a]蒽、N-亚硝基甲基脲和4-氨基联苯。采用改良的斯卡夫-布鲁姆-理查森方案对癌组织的组织病理学进行分级，并在10K cDNA微阵列上评估癌组织中的基因表达谱。无监督层次聚类分析显示，无论致癌剂如何，癌组织主要分为两个簇，这两个簇区分出具有不同组织病理学参数（分化程度、核分级、有丝分裂活性、上皮细胞生长模式和坏死）的两组。通过类别比较分析以及对所有癌组织（不考虑组织病理学）进行层次聚类，进一步表明基因表达谱根据致癌剂的不同存在统计学差异表达。这些发现表明，癌组织中的转录程序对于病因学因素具有独特性，并且尽管癌组织病理学存在差异，但在多种致癌物中均可观察到。利用微阵列分析在病理异质性乳腺癌组中识别病因特异性谱的能力，最终可能对于确定环境化学致癌物在人类乳腺癌风险中的作用具有重要价值。
