Department of Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE-40530, Göteborg, Sweden.
BMC Cancer. 2012 Aug 15;12:352. doi: 10.1186/1471-2407-12-352.
Development of breast cancer is a multistage process influenced by hormonal and environmental factors as well as by genetic background. The search for genes underlying this malignancy has recently been highly productive, but the etiology behind this complex disease is still not understood. In studies using animal cancer models, heterogeneity of the genetic background and environmental factors is reduced and thus analysis and identification of genetic aberrations in tumors may become easier. To identify chromosomal regions potentially involved in the initiation and progression of mammary cancer, in the present work we subjected a subset of experimental mammary tumors to cytogenetic and molecular genetic analysis.
Mammary tumors were induced with DMBA (7,12-dimethylbenz[a]anthrazene) in female rats from the susceptible SPRD-Cu3 strain and from crosses and backcrosses between this strain and the resistant WKY strain. We first produced a general overview of chromosomal aberrations in the tumors using conventional kartyotyping (G-banding) and Comparative Genome Hybridization (CGH) analyses. Particular chromosomal changes were then analyzed in more details using an in-house developed BAC (bacterial artificial chromosome) CGH-array platform.
Tumors appeared to be diploid by conventional karyotyping, however several sub-microscopic chromosome gains or losses in the tumor material were identified by BAC CGH-array analysis. An oncogenetic tree analysis based on the BAC CGH-array data suggested gain of rat chromosome (RNO) band 12q11, loss of RNO5q32 or RNO6q21 as the earliest events in the development of these mammary tumors.
Some of the identified changes appear to be more specific for DMBA-induced mammary tumors and some are similar to those previously reported in ACI rat model for estradiol-induced mammary tumors. The later group of changes is more interesting, since they may represent anomalies that involve genes with a critical role in mammary tumor development. Genetic changes identified in this work are at very small scales and thus may provide a more feasible basis for the identification of the target gene(s). Identification of the genes underlying these chromosome changes can provide new insights to the mechanisms of mammary carcinogenesis.
乳腺癌的发生是一个多阶段的过程，受到激素和环境因素以及遗传背景的影响。寻找导致这种恶性肿瘤的基因最近取得了丰硕的成果，但这种复杂疾病的病因仍不清楚。在使用动物癌症模型的研究中，遗传背景和环境因素的异质性降低，因此分析和鉴定肿瘤中的遗传异常可能变得更加容易。为了确定可能参与乳腺癌发生和发展的染色体区域，本研究使用 DMBA（7,12-二甲基苯并[a]蒽）在易感 SPRD-Cu3 品系的雌性大鼠中诱导产生乳腺肿瘤，并在该品系与抗性 WKY 品系之间进行杂交和回交，对这些肿瘤进行了细胞遗传学和分子遗传学分析。
我们首先使用常规核型分析（G 带）和比较基因组杂交（CGH）分析对肿瘤中的染色体异常进行了概述，然后使用内部开发的 BAC（细菌人工染色体）CGH 阵列平台对特定的染色体变化进行了更详细的分析。
通过常规核型分析，肿瘤似乎为二倍体，但 BAC CGH 阵列分析鉴定出肿瘤材料中存在几个亚微观染色体增益或丢失。基于 BAC CGH 阵列数据的致癌基因树分析表明，在这些乳腺肿瘤的发生发展中，RNO12q11 染色体带增益、RNO5q32 或 RNO6q21 缺失是最早的事件。
一些鉴定出的变化似乎更特异于 DMBA 诱导的乳腺肿瘤，而另一些则与 ACI 大鼠模型中雌激素诱导的乳腺肿瘤中报道的相似。后一组变化更有趣，因为它们可能代表涉及在乳腺肿瘤发生中具有关键作用的基因的异常。本研究中鉴定的遗传变化发生在非常小的范围内，因此可能为鉴定靶基因提供更可行的基础。鉴定这些染色体变化背后的基因可以为乳腺癌发生的机制提供新的见解。
