Regulation of retinoblastoma gene expression in hormone-dependent breast cancer.
Regulation of retinoblastoma gene expression in hormone-dependent breast cancer.
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DOI：
10.1210/endo.136.12.7588321
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发表时间：
1995-12
期刊：
影响因子：
4.8
通讯作者：
M. Gottardis;M. Saceda;P. García-Morales;Y. Fung;H. Solomon;P. F. Sholler;M. Lippman;M. Martin
中科院分区：
文献类型：
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作者：
M. Gottardis;M. Saceda;P. García-Morales;Y. Fung;H. Solomon;P. F. Sholler;M. Lippman;M. Martin
研究表明，患有视网膜母细胞瘤和骨肉瘤的儿童的母亲患乳腺癌的风险增加，这表明视网膜母细胞瘤易感性（Rb）基因产物在乳腺癌中的作用。我们现在发现，雌二醇降低Rb的表达在蛋白质和信使RNA（mRNA）水平的雌激素依赖性乳腺癌细胞系。用10（-9）M雌二醇处理MCF-7细胞48 h，Rb蛋白水平下降70%。核糖核酸酶保护试验表明，Rb mRNA的稳态水平下降50%，12小时，Rb mRNA下降70%，24小时。雌二醇处理对Rb基因转录速率或Rb mRNA稳定性没有影响，但导致细胞核中Rb mRNA稳态水平增加。雌二醇的作用可被10（-7）M 4-羟基他莫昔芬抑制。在没有雌二醇的情况下，抗雌激素4-羟基他莫昔芬和ICI 164，384使Rb mRNA比雌激素耗尽条件下增加50%。在其他雌激素依赖性乳腺癌细胞系中也存在Rb mRNA的Ehrman调控。胰岛素样生长因子I、胰岛素、孕激素和表皮生长因子对Rb表达无影响。总之，这些结果表明，雌二醇特异性地调节Rb易感基因产物在乳腺癌中的表达，通过发生在细胞核中的转录后机制。本研究结果提示，雌激素对Rb表达的负调控，而不是Rb的缺失或突变，可能在乳腺癌的发生中起重要作用。
Studies have shown an increased risk for breast cancer in the mothers of children suffering from retinoblastoma and osteosarcoma, suggesting a role for the retinoblastoma susceptibility (Rb) gene product in breast cancer. We now show that estradiol decreases the expression of Rb at the level of protein and messenger RNA (mRNA) in estrogen-dependent breast cancer cell lines. Treatment of MCF-7 cells with 10(-9) M estradiol for 48 h resulted in a 70% decrease in the level of Rb protein. Ribonuclease protection assays showed a 50% decrease in the steady state levels of Rb mRNA by 12 h and a 70% decrease in Rb mRNA by 24 h. Treatment with estradiol had no effect on the rate of Rb gene transcription or on Rb mRNA stability, but resulted in an increase in the steady state level of Rb mRNA in the nucleus. The effect of estradiol was inhibited by 10(-7) M 4-hydroxytamoxifen. In the absence of estradiol, the antiestrogens 4-hydroxytamoxifen and ICI 164,384 increased Rb mRNA by 50% over that in estrogen-depleted conditions. Estradiol regulation of Rb mRNA also occurred in other estrogen-dependent breast cancer cell lines. Insulin-like growth factor I, insulin, progestins, and epidermal growth factor had no effect on Rb expression. In summary, these results show that estradiol specifically regulates the expression of the Rb susceptibility gene product in hormone-dependent breast cancer by a posttranscriptional mechanism that occurs in the nucleus. The results from this study suggest that the negative regulation of Rb expression by estradiol, rather than Rb loss or mutation, may play an important role in breast carcinogenesis.