Molis T M, Spriggs L L, Jupiter Y, Hill S M
Department of Anatomy, Tulane University School of Medicine, New Orleans, LA 70112, USA.
J Pineal Res. 1995 Mar;18(2):93-103. doi: 10.1111/j.1600-079x.1995.tb00146.x.
The growth-inhibitory actions of the pineal hormone, melatonin, on human breast tumor cells and the possible association between this inhibition and melatonin's down-regulation of the estrogen receptor (ER) expression were examined in the ER-positive, estrogen-responsive MCF-7 human breast tumor cell line. As previously reported, melatonin dramatically inhibits the growth of these breast tumor cells and down-regulates ER levels in these cells, suggesting that the modulation of ER may be an important mechanism by which melatonin inhibits breast cancer cell growth. In the present studies, Northern blot analysis was used to examine the expression of estrogen-regulated transcripts known to be involved in estrogen's mitogenic actions. Melatonin, at a physiologic concentration (10(-9) M), rapidly, significantly, and, in some cases, transiently elevated the steady-state mRNA levels of growth stimulatory products such as TGF alpha, c-myc, and pS2, which are normally up-regulated in response to estrogen. Conversely, melatonin decreased the expression of other factors normally up-regulated by estrogen, such as progesterone receptor and c-fos. Significant stimulation of the expression of the growth-inhibitory factor TGF beta was seen with melatonin treatment, potentially supporting the concept that melatonin's growth-inhibitory activity is mediated through the breast tumor cells' estrogen-response pathway. The early regulation of many of these products by melatonin suggests that mechanisms more rapid than the down-regulation of ER are important in melatonin's modulation of their expression. However, the long-term modulation of these transcripts (12-48 hr) may be heavily influenced by melatonin's down-regulation of ER expression. These results clearly define the need for additional in depth studies to dissect the cellular events leading to melatonin-induced growth inhibition in breast tumor cells.
在雌激素受体（ER）阳性、雌激素反应性的MCF-7人乳腺肿瘤细胞系中，研究了松果体激素褪黑素对人乳腺肿瘤细胞的生长抑制作用，以及这种抑制作用与褪黑素下调雌激素受体（ER）表达之间的可能关联。如先前报道，褪黑素显著抑制这些乳腺肿瘤细胞的生长，并下调这些细胞中的ER水平，这表明ER的调节可能是褪黑素抑制乳腺癌细胞生长的重要机制。在本研究中，采用Northern印迹分析来检测已知参与雌激素促有丝分裂作用的雌激素调节转录本的表达。褪黑素在生理浓度（10^(-9) M）下，迅速、显著地，并且在某些情况下短暂地提高了生长刺激产物如转化生长因子α（TGFα）、原癌基因c-myc和pS2的稳态mRNA水平，这些产物通常在雌激素作用下上调。相反，褪黑素降低了其他通常在雌激素作用下上调的因子的表达，如孕激素受体和原癌基因c-fos。褪黑素处理后可见生长抑制因子TGFβ的表达受到显著刺激，这可能支持了褪黑素的生长抑制活性是通过乳腺肿瘤细胞的雌激素反应途径介导的这一概念。褪黑素对许多这些产物的早期调节表明，比ER下调更快的机制在褪黑素对其表达的调节中很重要。然而，这些转录本的长期调节（12 - 48小时）可能受到褪黑素下调ER表达的严重影响。这些结果清楚地表明需要进行更多深入研究，以剖析导致褪黑素诱导乳腺肿瘤细胞生长抑制的细胞事件。
