Multiple genetic changes are associated with mammary tumorigenesis in Brca1 conditional knockout mice
Multiple genetic changes are associated with mammary tumorigenesis in Brca1 conditional knockout mice
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DOI：
10.1038/sj.onc.1204929
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发表时间：
2001-11-08
期刊：
影响因子：
8
通讯作者：
Deng, CX
中科院分区：
文献类型：
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作者：
Brodie, SG;Xu, XL;Deng, CX
肿瘤抑制基因BRCA 1的生殖系突变使女性易患乳腺癌，然而该基因的体细胞突变很少在散发性癌症中检测到。为了理解这一现象，我们研究了携带条件性破坏乳腺上皮中的Brca 1的小鼠模型，无论是p53野生型（wt）或杂合背景。虽然p53（+/-）突变显着加速肿瘤发生，这两种菌株发展乳腺肿瘤的随机方式，表明多种因素，除了p53突变，可能参与Brca 1相关的肿瘤发生。Brca 1乳腺肿瘤的一个独特特征是其高度多样的组织病理学，伴有严重的染色体异常。肿瘤还显示出广泛的遗传/分子改变，包括在大多数肿瘤中ErbB 2、c-Myc、p27和Cyclin D1的过表达，而它们实际上是ER α和p16阴性的。还鉴定了涉及p53的易位，其导致异常RNA和蛋白质产物。此外，我们从乳腺肿瘤中产生了细胞系，发现这些细胞保留了原发性肿瘤中发现的许多遗传变化，这表明这些基因可能是Brca 1相关肿瘤发生的参与者。尽管它们的不同形态，所有培养的肿瘤细胞都是他莫昔芬耐药的，但对阿霉素或放射高度敏感，这表明这些方法将有效治疗这种疾病。
Germline mutations in the tumor suppressor gene BRCA1 predispose women to breast cancer, however somatic mutations in the gene are rarely detected in sporadic cancers. To understand this phenomenon, we examined mouse models carrying conditional disruption of Brca1 in mammary epithelium in either p53 wild type (wt) or heterozygous backgrounds. Although a p53(+/-) mutation significantly accelerated tumorigenesis, both strains developed mammary tumors in a stochastic fashion, suggesting that multiple factors, in addition to p53 mutations, may be involved in Brca1 related tumorigenesis. A unique feature of Brca1 mammary tumors is their highly diverse histopathology accompanied by severe chromosome abnormalities. The tumors also display extensive genetic/molecular alterations, including overexpression of ErbB2, c-Myc, p27 and Cyclin D1 in the majority of tumors, while they were virtually ER alpha and p16 negative. Translocations involving p53 were also identified which lead to abnormal RNA and protein products. In addition, we generated cell lines from mammary tumors and found that the cells retained many of the genetic changes found in the primary tumors, suggesting that these genes may be players in Brca1-associated tumorigenesis. Despite their distinct morphology, all cultured tumor cells were Tamoxifen resistant but highly sensitive to Doxorubicin or irradiation, suggesting that these methods would be effective in treatment of this disease.