Global expression profiling identifies signatures of tumor virulence in MMTV-PyMT-transgenic mice: Correlation to human disease
Global expression profiling identifies signatures of tumor virulence in MMTV-PyMT-transgenic mice: Correlation to human disease
复制标题
DOI：
10.1158/0008-5472.can-04-0242
复制
发表时间：
2004-09-01
期刊：
影响因子：
11.2
通讯作者：
Liu, ET
中科院分区：
文献类型：
--
作者：
Qiu, TH;Chandramouli, GVR;Liu, ET
FVB/N-TG(MMTV-PYMT)(634-1)转基因小鼠发生多灶性乳腺肿瘤，肺转移发生率高。我们以前已经证明，与FVB/NJ纯合亲本相比，来自转基因阳性F1后代的乳腺肿瘤，特别是近交系菌株，其潜伏期、肿瘤生长速度和转移率都发生了变化。为了确定可能在改变MMTV-PYMT肿瘤生物学行为中起关键作用的表达基因，我们对发生在亲代FVB/NJ背景中的乳腺肿瘤以及与I/LnI、LP/J、Molf/Ei和NZB/B1NJ小鼠杂交的F1后代的表达谱进行了详细的比较分析。与正常乳腺组织相比，所有5株乳腺肿瘤的基因表达谱显示与细胞生长相关的基因(如Cks1和CDC25C)表达上调，细胞黏附分子表达下调，许多以前与人类乳腺癌相关的基因如STAT2、CD24抗原、明胶蛋白和Lipocalin2。采用基因芯片显著性分析(SAM)和单因素方差分析方法，筛选5种不同基因间差异表达显著的基因。确定了三种可定义的肿瘤分组：(A)来自LP/J F1和Molf/EI F1株的肿瘤，其中肿瘤的生长和扩散受到抑制，潜伏期延长；(B)来自FVB/NJ亲本株和I/LnJ F1基因组背景的最具侵袭性的肿瘤；以及(C)来自NZB/B1NJ-F1杂交株的中等毒力表型的肿瘤。这些基于阵列的评估与使用“毒力”指数的综合表型排名有很好的相关性。与小鼠高转移率相关的基因表达特征包含与最近描述的预测人类肿瘤转移的特征基因集相同的17个基因(1)，17个基因中有16个表现出与人类转移相关的相同的表达方向变化。这些结果表明，对小鼠肿瘤发生模型的遗传分析可能与人类癌症高度相关，肿瘤的转移表型可能受宿主的种系遗传配置的影响。
FVB/N-Tg (MMTV-PyMT) (634Mul)-transgenic mice develop multifocal mammary tumors with a high incidence of pulmonary metastasis. We have demonstrated previously that mammary tumors derived from transgene-positive F1 progeny in particular inbred strains display altered latency, tumor growth rates, and metastatic rates when compared with the FVB/NJ homozygous parent. To identify genes with expression that might be critical in modifying the biological behavior of MMTV-PyMT tumors, we performed a detailed comparative analysis of expression profiles from mammary tumors arising in the parental FVB/NJ background and F1 progeny from crosses with I/Lni, LP/J, MOLF/Ei, and NZB/B1NJ mice. Compared with normal mammary glands, gene expression profiles of tumors from all five strains exhibited up-regulation of genes involved in cell growth (e.g., Cks1 and CDC25C) and down-regulation of cell adhesion molecules, with many genes associated previously with human breast cancer such as STAT2, CD24 antigen, gelsolin, and lipocalin2. To identify genes with significant variation in expression between the five different genotypes, significance analysis of microarrays (SAM) and one-way ANOVA were used. Three definable groupings of tumors were identified: (a) tumors derived in the LP/J F1 and MOLF/Ei F1 strains in which tumor growth and dissemination are suppressed and latency prolonged; (b) the most aggressive tumors from the FVB/NJ parental strain and I/LnJ F1 genomic backgrounds; and (c) an intermediate virulence phenotype with tumors from NZB/B1NJ-F1 crosses. These array based assessments correlated well with a composite phenotype ranking using a "virulence" index. The gene expression signature that is associated with a high metastatic rate in the mouse contains the same 17 genes described recently as the signature gene set predictive of metastasis in human tumors (1) with 16 of the 17 genes exhibiting the same directional change in expression associated with human metastases. These results demonstrate that the genetic analysis of mouse models of tumorigenesis may be highly relevant to human cancer and that the metastatic phenotype of a tumor may be affected by the germline genetic configuration of the host.