Adamovic Tatjana, Roshani Leyla, Chen Lei, Schaffer Beverly S, Helou Khalil, Levan Göran, Olsson Björn, Shull James D
CMB-Genetics, Göteborg University, SE 40530 Göteborg, Sweden.
Genes Chromosomes Cancer. 2007 May;46(5):459-69. doi: 10.1002/gcc.20428.
Estrogens play an important role in breast cancer etiology and the ACI rat provides a novel animal model for defining the mechanisms through which estrogens contribute to mammary cancer development. In crossing experiments between the susceptible ACI strain and two resistant strains, COP (Copenhagen) and BN (Brown Norway), several quantitative trait loci (QTL) that affect development of 17beta-estradiol (E2)-induced mammary tumors have been defined. Using comparative genomic hybridization (CGH), we have analyzed cytogenetic aberrations in E2-induced mammary cancers and have found clear patterns of nonrandom chromosomal involvement. Approximately two thirds of the tumors exhibited copy number changes. Losses of rat chromosome 5 (RNO5) and RNO20 were particularly common, and it was found that these two aberrations often occurred together. A third recurrent aberration involving proximal gain and distal loss in RNO6 probably defined a distinct subgroup of tumors, since it never occurred in combination with RNO5 loss. Interestingly, QTL with powerful effects on mammary cancer development have been mapped to RNO5 and RNO6. These findings suggest that there were at least two genetic pathways to tumor formation in this rat model of E2-induced mammary cancer. By performing CGH on mammary tumors from ACI rats, F1 rats from crosses between the ACI and COP or BN strains and ACI.BN-Emca8 congenic rats, which carry the BN allele of the Emca8 QTL on RNO5 on the ACI genetic background, we were able to determine that the constitution of the germ line influences the pattern of chromosomal aberrations.
雌激素在乳腺癌病因学中发挥着重要作用，而ACI大鼠为确定雌激素促进乳腺癌发展的机制提供了一种新的动物模型。在易感的ACI品系与两个抗性品系COP（哥本哈根）和BN（棕色挪威）的杂交实验中，已确定了几个影响17β-雌二醇（E2）诱导的乳腺肿瘤发展的数量性状基因座（QTL）。使用比较基因组杂交（CGH），我们分析了E2诱导的乳腺癌中的细胞遗传学畸变，并发现了非随机染色体参与的清晰模式。大约三分之二的肿瘤表现出拷贝数变化。大鼠5号染色体（RNO5）和RNO20的缺失尤为常见，并且发现这两种畸变经常同时发生。涉及RNO6近端增益和远端缺失的第三种复发性畸变可能定义了一个不同的肿瘤亚组，因为它从未与RNO5缺失同时发生。有趣的是，对乳腺癌发展有强大影响的QTL已被定位到RNO5和RNO6。这些发现表明，在这个E2诱导的乳腺癌大鼠模型中，至少有两条肿瘤形成的遗传途径。通过对来自ACI大鼠、ACI与COP或BN品系杂交的F1大鼠以及ACI.BN-Emca8同源大鼠（在ACI遗传背景上携带RNO5上Emca8 QTL的BN等位基因）的乳腺肿瘤进行CGH，我们能够确定种系的构成会影响染色体畸变的模式。
