Environmental carcinogens and p53 tumor-suppressor gene interactions in a transgenic mouse model for mammary carcinogenesis.
Environmental carcinogens and p53 tumor-suppressor gene interactions in a transgenic mouse model for mammary carcinogenesis.
复制标题
环境致癌物和 p53 肿瘤抑制基因在乳腺癌转基因小鼠模型中的相互作用。
DOI：
10.1002/em.10064
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发表时间：
2002
影响因子：
2.8
通讯作者：
Donehower,Larry
中科院分区：
文献类型：
--
作者：
Medina,Daniel;Ullrich,Robert;Meyn,Raymond;Wiseman,Roger;Donehower,Larry
小鼠乳腺肿瘤发生受多种外源性因子的极大影响，例如MMTV、化学致癌物（即，多环芳烃）和辐射，以及内源性/生理因素，如类固醇激素，肿瘤抑制基因（即，Brca 1/2，p53）和修饰基因的基因产物。在小鼠模型中，最常用的化学致癌物是7，12-二甲基苯并[a]蒽（DMBA），它可以激活Ha‐ ras基因，但不会改变p53肿瘤抑制基因。然而，在p53基因改变的现有背景下，低剂量的DMBA具有强烈的致癌作用。使用乳腺中p53基因缺失的转基因模型系统，我们检查了低剂量或生理剂量下各种外部因素和内部因素的致癌作用。这些因素包括DMBA、γ辐射、Brca 2杂合性和类固醇激素。所有试剂/因子增加p53无效乳腺细胞的致瘤反应，即使在p53野生型乳腺细胞中未观察到致瘤反应的条件下。类固醇激素孕酮的致癌作用最强。大多数肿瘤为高度非整倍体，由核高级别细胞组成。利用阵列技术研究了与高致瘤性相关的非整倍体和继发事件的机制。这些结果表明，在潜在的遗传不稳定性的背景下，非常低剂量的环境诱变剂和有丝分裂原可以产生强烈的共致癌作用。Environ.摩尔变异体39：178-183，2002.© 2002 Wiley利斯公司
Mouse mammary tumorigenesis is greatly influenced by a variety of exogenous agents, such as MMTV, chemical carcinogens (i.e., polycyclic aromatic hydrocarbons), and radiation, as well as by endogenous/physiological factors, such as steroid hormones, tumor‐suppressor genes (i.e.,Brca1/2,p53), and gene products of modifier genes. In the mouse model, the most frequently used chemical carcinogen has been 7,12‐dimethylbenz[a]anthracene (DMBA), which activates the Ha‐rasgene but does not alter thep53tumor‐suppressor gene. However, on an existing background ofp53gene alteration, low doses of DMBA are strongly cocarcinogenic. Using a transgenic model system, in which thep53gene was deleted in the mammary gland, we examined the carcinogenic effects of a variety of external agents and internal factors given at either low doses or physiological doses. These agents/factors included DMBA, γ‐radiation,Brca2heterozygosity, and steroid hormones. All agents/factors increased the tumorigenic response of the p53 null mammary cells, even under conditions where no tumorigenic response was observed in the p53 wildtype mammary cell. The strongest cocarcinogenic effect was observed with the steroid hormone progesterone. The majority of tumors were highly aneuploid and composed of nuclear igh‐grade cells. The mechanism for the aneuploidy and secondary events associated with high tumorigenicity were examined using array technology. These results demonstrate that, on a background of underlying genetic instability, very low doses of environmental mutagens and mitogens can produce strong cocarcinogenic effects. Environ. Mol. Mutagen. 39:178–183, 2002. © 2002 Wiley‐Liss, Inc.