Fan S, Meng Q, Gao B, Grossman J, Yadegari M, Goldberg I D, Rosen E M
Department of Radiation Oncology, Long Island Jewish Medical Center, The Long Island Campus for the Albert Einstein College of Medicine, New Hyde Park, New York 11040, USA.
Cancer Res. 2000 Oct 15;60(20):5635-9.
Epidemiological studies suggest that moderate alcohol consumption increases the risk of breast cancer, and that alcohol combined with estrogen replacement therapy may synergistically enhance the risk. However, the mechanism(s) of alcohol-induced mammary cancer is unknown. In human breast cancer cell lines, we found that ethanol (EtOH) caused a dose-dependent increase of up to 10- to 15-fold in the transcriptional activity of the liganded estrogen receptor (ER-alpha), but did not activate the nonliganded receptor. Significant stimulation of ER-alpha activity was observed at EtOH concentrations comparable with or less than blood alcohol levels associated with intoxication and at doses below the threshold for in vitro cytotoxicity. These findings may be explained, in part, by an EtOH-induced down-regulation of the expression of BRCA1, a potent inhibitor of ER-alpha activity, and, in part, by a modest increase in the ER-alpha levels. Our findings suggest that inactivation of BRCA1 and increased estrogen-responsiveness might contribute to alcohol-induced breast cancer.
流行病学研究表明，适度饮酒会增加患乳腺癌的风险，并且酒精与雌激素替代疗法联合使用可能会协同增加这种风险。然而，酒精诱发乳腺癌的机制尚不清楚。在人乳腺癌细胞系中，我们发现乙醇（EtOH）可使配体化雌激素受体（ER-α）的转录活性呈剂量依赖性增加，最高可达10至15倍，但不会激活未配体化的受体。在与中毒相关的血液酒精水平相当或更低的EtOH浓度下以及低于体外细胞毒性阈值的剂量下，观察到了对ER-α活性的显著刺激。这些发现部分可以通过EtOH诱导的BRCA1表达下调来解释，BRCA1是ER-α活性的有效抑制剂，部分可以通过ER-α水平的适度增加来解释。我们的研究结果表明，BRCA1的失活和雌激素反应性增加可能导致酒精诱发的乳腺癌。
