Sheikh M S, Shao Z M, Hussain A, Fontana J A
Department of Medicine, University of Maryland Cancer Center, University of Maryland School of Medicine, Baltimore 21201.
Cancer Res. 1993 Jul 15;53(14):3226-8.
The human p53-binding protein murine double minute 2 (MDM2) is believed to function as a negative regulator of p53. The MDM2 gene was cloned and sequenced only recently and was found to be amplified in a variety of sarcomas. Although mutations in the p53 gene have been shown to occur in human breast carcinoma (HBC), no information is available on MDM2 gene expression in HBC. In this study we report for the first time that the MDM2 gene is differentially expressed in HBC. Our results demonstrate a correlation between the estrogen receptor (ER) status and the MDM2 mRNA levels. In contrast to the ER-negative cell lines, all the ER-positive cell lines were found to express higher levels of MDM2 mRNA. ER-positive ZR-75 cells express 30-fold higher levels of MDM2 mRNA than does the ER-negative cell line Hs578T. Estrogen enhanced albeit modestly the MDM2 mRNA levels in ER-positive MCF-7 cells. Estrogen enhancement of MDM2 mRNA levels was also observed in ER-negative MDA-MB-231 cells transfected with functional ERs. Our data thus suggest that estrogen may play an important role in HBC growth stimulation by modulating the expression of MDM2, which in turn may inactivate the p53 function.
人类p53结合蛋白小鼠双微体2（MDM2）被认为是p53的负调节因子。MDM2基因直到最近才被克隆和测序，并且发现它在多种肉瘤中被扩增。尽管已表明p53基因的突变发生在人类乳腺癌（HBC）中，但关于HBC中MDM2基因表达的信息却尚无报道。在本研究中，我们首次报道MDM2基因在HBC中差异表达。我们的结果表明雌激素受体（ER）状态与MDM2 mRNA水平之间存在相关性。与ER阴性细胞系相反，所有ER阳性细胞系均被发现表达更高水平的MDM2 mRNA。ER阳性的ZR-75细胞表达的MDM2 mRNA水平比ER阴性细胞系Hs578T高30倍。雌激素虽作用适度但可提高ER阳性MCF-7细胞中MDM2 mRNA的水平。在用功能性ER转染的ER阴性MDA-MB-231细胞中也观察到雌激素对MDM2 mRNA水平的增强作用。因此，我们的数据表明雌激素可能通过调节MDM2的表达在HBC生长刺激中发挥重要作用，而MDM2反过来可能使p53功能失活。
