Acquisition of Genomic Alterations During Mammary Gland

采用基因芯片技术检测了正常雌性Sprague-Dawley大鼠乳腺和肉源致癌物2-氨基-1-甲基-6-苯基咪唑[4,5-b]吡啶（PhIP）和强效致癌物7,12-二甲基苯[a]蒽（DMBA）诱导的肿瘤的基因表达谱。用大鼠6.9k cDNA芯片检测了初乳、妊娠和哺乳期大鼠的管状乳头状癌和正常乳腺。虽然在组织学上相同，但PhIP-和dmba诱导的癌可以通过cDNA表达的分层聚类和多维尺度分析来区分。此外，21个克隆在PhIP-和dmba诱导的癌中表达有统计学差异（f检验，p<0.05）。数据表明，不同的化学致癌物在乳腺癌中诱导独特的基因表达模式。在癌症中发现的特定化学致癌物质相关cDNA阵列谱可能最终适用于更好地了解癌症病因。PhIP-和dmba诱导的癌在cDNA表达谱上也有相似之处。通过比较PhIP- + dmba诱导的肿瘤与正常大鼠乳腺（任何分化阶段）的表达，发现172个克隆存在差异表达。通过cDNA微阵列分析（并通过免疫组织化学和western blot分析进一步验证）显示癌中表达增加的基因包括cyclin D1、PDGF-A链、视黄醇结合蛋白1、禁止蛋白和转录因子STAT5A。PhIP-和dmba诱导的癌之间基因表达的相似性提出了一种可能性，即不管致癌起始剂是什么，大鼠乳腺转化的几种分子途径都是维持不变的。

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.