Clarke C L, Roman S D, Graham J, Koga M, Sutherland R L
Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, New South Wales, Australia.
J Biol Chem. 1990 Jul 25;265(21):12694-700.
Data are presented which document the first known effect of retinoic acid on progesterone receptor (PR) gene expression. Treatment of T-47D human breast cancer cells with retinoic acid for 48 h resulted in a marked concentration-dependent decrease in the level of PR mRNA and immunoreactive protein which was similar to the known effect of progestins on these parameters. Retinoic acid, however, did not bind to PR, nor did it cause the previously demonstrated increase in PR molecular weight observed after progestin exposure. When T-47D cells were treated with retinoic acid for 6 h rather than 48 h, no reduction in the level of PR protein was noted at any retinoic acid concentration whereas the effects of retinoic acid on PR mRNA at 6 and 48 h were the same. Examination of the time course of the effects of retinoic acid revealed a rapid decrease in PR mRNA levels detectable 1 h after and maximal 6 h after treatment of T-47D cells with retinoic acid. These effects of retinoic acid contrasted with previously demonstrated progestin effects on PR mRNA which were not apparent until 3 h after and were not maximal until 12 h after treatment. As expected, the PR protein concentration was unaffected for at least 6 h but was maximally decreased 24-48 h after retinoic acid treatment. In summary, retinoic acid treatment of T-47D cells caused a decrease in the cellular PR concentration by decreasing levels of receptor mRNA and protein, suggesting that retinoic acid is capable of modulating sensitivity to progestins in human breast cancer cells.
本文呈现的数据记录了视黄酸对孕激素受体（PR）基因表达的首个已知效应。用视黄酸处理T-47D人乳腺癌细胞48小时后，PR mRNA水平和免疫反应性蛋白水平显著降低，呈浓度依赖性，这与孕激素对这些参数的已知效应相似。然而，视黄酸不与PR结合，也不会导致孕激素暴露后观察到的PR分子量增加。当用视黄酸处理T-47D细胞6小时而非48小时时，在任何视黄酸浓度下均未观察到PR蛋白水平降低，而视黄酸在6小时和48小时对PR mRNA的影响相同。对视黄酸作用的时间进程进行检查发现，用视黄酸处理T-47D细胞1小时后可检测到PR mRNA水平迅速下降，6小时后降至最大。视黄酸的这些作用与先前证明的孕激素对PR mRNA的作用形成对比，孕激素的作用直到处理后3小时才显现，12小时后才达到最大。正如预期的那样，PR蛋白浓度至少6小时未受影响，但在视黄酸处理后24 - 48小时降至最大。总之，视黄酸处理T-47D细胞通过降低受体mRNA和蛋白水平导致细胞PR浓度降低，这表明视黄酸能够调节人乳腺癌细胞对孕激素的敏感性。
