Loss of heterozygosity occurs via mitotic recombination in Trp53+/- mice and associates with mammary tumor susceptibility of the BALB/c strain
Loss of heterozygosity occurs via mitotic recombination in Trp53+/- mice and associates with mammary tumor susceptibility of the BALB/c strain
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DOI：
10.1158/0008-5472.can-03-3435
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发表时间：
2004-08-01
期刊：
影响因子：
11.2
通讯作者：
Jerry, DJ
中科院分区：
文献类型：
--
作者：
Blackburn, AC;McLary, SC;Jerry, DJ
杂合性缺失（LOH）通常发生在癌症中，引起肿瘤抑制基因的破坏并促进肿瘤进展。BALB/c-Trp53（+/-）小鼠是Li-Fraumeni综合征的模型，在患者中表现出高频率的乳腺肿瘤和其他肿瘤类型。然而，乳腺肿瘤和LOH的频率在Trp53（+/-）小鼠菌株之间存在差异，乳腺肿瘤仅在BALB/c遗传背景下发生，LOH的频率很高，而Trp53（+/-）小鼠在129/Sv或（C57BL/6 x 129/Sv）混合背景下发生乳腺肿瘤的频率非常低，Trp53的LOH仅在接近50%的肿瘤中出现。我们对几种遗传背景的Trp53（+/-）小鼠肿瘤进行了研究，以探讨LOH在BALB/c-Trp53（+/-）乳腺肿瘤中的机制。通过Southern blotting， 96% (24 / 25) BALBIc-Trp53（+/-）乳腺肿瘤显示Trp53的LOH。核型分析表明，缺乏11号染色体拷贝的细胞在所有5个乳腺肿瘤中都存在，但并不总是优势群体。这5个肿瘤的比较基因组杂交分析表明整个11号染色体缺失或保留。因此，11号染色体内的染色体丢失或缺失不能解释Southern blotting观察到的LOH。对（C57BL/6 x BALB/c） F1-Trp53（+/-）乳腺肿瘤的简单序列长度多态性分析表明，LOH发生在多个位点上，并且保留了母本和父本等位基因的组合，表明有丝分裂重组是LOH最可能的机制。BALB/c小鼠的非乳腺肿瘤也显示出高频率的LOH(26 / 85%)，这表明它不是乳腺肿瘤特有的现象，而是BALB/c菌株的特征。在（C57BL/6 X BALB/c） F1-Trp53（+/-）小鼠中，93%（14 / 14）的肿瘤中存在LOH，表明LOH的高频率是显性遗传性状。因此，在BALB/c-Trp53（+/-）乳腺肿瘤中，Trp53的高频率LOH通过有丝分裂重组发生，是与（C57BL/6 X BALB/c） F1-Trp53（+/-）小鼠乳腺肿瘤发生相关的显性遗传性状。这些结果进一步暗示双链DNA断裂修复机制是乳腺肿瘤发生的重要因素。
Loss of heterozygosity (LOH) occurs commonly in cancers causing disruption of tumor suppressor genes and promoting tumor progression. BALB/c-Trp53(+/-) mice are a model of Li-Fraumeni syndrome, exhibiting a high frequency of mammary tumors and other tumor types seen in patients. However, the frequency of mammary tumors and LOH differs among strains of Trp53(+/-) mice, with mammary tumors occurring only on a BALB/c genetic background and showing a high frequency of LOH, whereas Trp53(+/-) mice on a 129/Sv or (C57BL/6 x 129/Sv) mixed background have a very low frequency of mammary tumors and show LOH for Trp53 in only similar to50% of tumors. We have performed studies on tumors from Trp53(+/-) mice of several genetic backgrounds to examine the mechanism of LOH in BALB/c-Trp53(+/-) mammary tumors. By Southern blotting, 96% (24 of 25) of BALBIc-Trp53(+/-) mammary tumors displayed LOH for Trp53. Karyotype analysis indicated that cells lacking one copy of chromosome 11 were present in all five mammary tumors analyzed but were not always the dominant population. Comparative genomic hybridization analysis of these five tumors indicated either loss or retention of the entire chromosome 11. Thus chromosome loss or deletions within chromosome 11 do not account for the LOH observed by Southern blotting. Simple sequence length polymorphism analysis of (C57BL/6 x BALB/c) F1-Trp53(+/-) mammary tumors showed that LOH occurred over multiple loci and that a combination of maternal and paternal alleles were retained, indicating that mitotic recombination is the most likely mechanism of LOH. Nonmammary tumors of BALB/c mice also showed a high frequency of LOH (22 of 26, 85%) indicating it was not a mammary tumor specific phenomenon but rather a feature of the BALB/c strain. In (C57BL/6 X BALB/c) F1-Trp53(+/-) mice LOH was observed in 93% (13 of 14) of tumors, indicating that the high frequency of LOH was a dominant genetic trait. Thus the high frequency of LOH for Trp53 in BALB/c-Trp53(+/-) mammary tumors occurs via mitotic recombination and is a dominant genetic trait that associates with the occurrence of mammary tumors in (C57BL/6 X BALB/c) F1-Trp53(+/-) mice. These results further implicate double-strand DNA break repair machinery as important contributors to mammary tumorigenesis.