Acquisition of Genomic Alterations During Mammary Gland

采用基因芯片技术检测了正常雌性SD大鼠乳腺组织和熟肉源致癌物2-氨基-1-甲基-6-苯基咪唑[4，5-B]吡啶（PhIP）和强致癌物7，12-二甲基苯并[a]蒽（DMBA）诱发的乳腺癌组织中基因表达谱。应用大鼠6.9kcDNA芯片检测了未孕、妊娠和哺乳期大鼠的乳头状癌和正常乳腺组织。虽然组织学相同，PhIP和DMBA诱导的癌可以区分的cDNA表达的层次聚类和多维尺度分析。此外，21个克隆的表达在PhIP和DMBA诱导的癌之间具有统计学差异（F检验，p<0.05）。这些数据表明，不同的化学致癌物诱导乳腺癌独特的基因表达模式。在癌症中发现的特定化学致癌物相关的cDNA阵列谱可能最终适用于更好地理解癌症病因。PhIP和DMBA诱导的癌在cDNA表达谱上也有相似之处。通过比较癌（PhIP-加DMBA-诱导的）与正常大鼠乳腺（在任何分化阶段）中的表达，发现172个克隆差异表达。通过cDNA微阵列分析（并通过免疫组织化学和蛋白质印迹分析进一步验证）显示癌中表达增加的基因包括细胞周期蛋白D1、PDGF-A链、视黄醇结合蛋白1、抑制素和转录因子STAT 5A。PhIP和DMBA诱导的癌之间的基因表达的相似性提高了大鼠乳腺转化的几个分子途径保持不考虑致癌起始剂的可能性。

cDNA microarray analysis was used to examine gene expression profiles in normal female Sprague-Dawley rat mammary gland and in carcinomas induced by the cooked-meat derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and the potent experimental carcinogen 7,12-dimethylbenz[a]anthracene (DMBA). Tubulopapillary carcinomas and normal mammary gland from virgin, pregnant and lactating rats were examined on a rat 6.9k cDNA microarray. Although histologically identical, PhIP- and DMBA-induced carcinomas could be distinguished by hierarchical clustering and multi-dimensional scaling analyses of cDNA expression. In addition, the expression of 21 clones was statistically different between PhIP- and DMBA-induced carcinomas (F-test, p<0.05). The data indicate that distinct chemical carcinogens induce unique gene expression patterns in mammary gland carcinomas. The specific chemical carcinogen-associated cDNA array profiles found in carcinomas may ultimately be applicable to better understanding cancer etiology. PhIP- and DMBA-induced carcinomas also shared similarities in cDNA expression profiles. By comparing the expression in carcinomas (PhIP- plus DMBA-induced) with normal rat mammary gland (at any stage of differentiation), 172 clones were found to be differentially expressed. Genes showing increased expression in carcinomas by cDNA microarray analysis (and further validated by immunohistochemistry and western blot analysis) include cyclin D1, PDGF-A chain, retinol binding protein 1, prohibitin, and the transcription factor STAT5A. The similarities in gene expression between PhIP- and DMBA-induced carcinomas raise the possibility that several molecular pathways for rat mammary gland transformation are maintained irrespective of the carcinogenic initiating agent.