Impaired p53 function leads to centrosome amplification, acquired ERα phenotypic heterogeneity and distant metastases in breast cancer MCF-7 xenografts
Impaired p53 function leads to centrosome amplification, acquired ERα phenotypic heterogeneity and distant metastases in breast cancer MCF-7 xenografts
复制标题
DOI：
10.1038/onc.2008.18
复制
发表时间：
2008-06-01
期刊：
影响因子：
8
通讯作者：
Salisbury, J. L.
中科院分区：
文献类型：
--
作者：
D'Assoro, A. B.;Busby, R.;Salisbury, J. L.
在这项研究中，我们建立了一个 MCF-7 异种移植模型，模拟人类乳腺癌的进展，其典型特征是 p53 完整性丧失、中心体扩增、获得性雌激素受体 (ER α) 异质性、Mdm2 过度表达以及从原发肿瘤到远处器官的转移扩散。 p53功能被消除的MCF-7细胞(vMCF-7D(np53))在体外维持核ERa表达和正常中心体特征。然而，在有丝分裂原刺激后，它们出现中心体扩增和异常有丝分裂纺锤体频率更高。中心体扩增依赖于 cdk2/细胞周期蛋白活性，因为用小分子抑制剂 SU9516 治疗可抑制中心粒重复。与亲代MCF-7细胞相比，当作为异种移植物引入裸鼠时，来自vMCF-7（DNp53）细胞系的肿瘤出现了显着改变的表型，其特征是肿瘤生长增加、肿瘤组织病理学等级更高、中心体扩增、核ERa表达缺失、Mdm-2癌蛋白表达增加以及对抗雌激素他莫昔芬的抗性。重要的是，虽然MCF-7异种移植物没有发生远处转移，但源自vMCF-7（DNp53）细胞的原发性肿瘤引起了肺转移。总而言之，这些观察结果表明，p53 功能的废除和随之而来的 G1/S 细胞周期转变的失调导致中心体扩增，从而导致乳腺癌进展。
In this study, we establish an MCF-7 xenograft model that mimics the progression of human breast carcinomas typified by loss of p53 integrity, development of centrosome amplification, acquired estrogen receptor (ER alpha) heterogeneity, overexpression of Mdm2 and metastatic spread from the primary tumor to distant organs. MCF-7 cells with abrogated p53 function (vMCF-7D(np53)) maintained nuclear ERa expression and normal centrosome characteristics in vitro. However, following mitogen stimulation, they developed centrosome amplification and a higher frequency of aberrant mitotic spindles. Centrosome amplification was dependent on cdk2/cyclin activity since treatment with the small molecule inhibitor SU9516 suppressed centriole reduplication. In contrast to the parental MCF-7 cells, when introduced into nude mice as xenografts, tumors derived from the vMCF-7(DNp53) cell line developed a strikingly altered phenotype characterized by increased tumor growth, higher tumor histopathology grade, centrosome amplification, loss of nuclear ERa expression, increased expression of Mdm-2 oncoprotein and resistance to the antiestrogen tamoxifen. Importantly, while MCF-7 xenografts did not develop distant metastases, primary tumors derived from vMCF-7(DNp53) cells gave rise to lung metastases. Taken together, these observations indicate that abrogation of p53 function and consequent deregulation of the G1/S cell cycle transition leads to centrosome amplification responsible for breast cancer progression.