Bilallelic inactivation of retinoic acid receptor β2 gene by epigenetic change in breast cancer

越来越多的证据支持视黄酸受体β2 （RAR β2）是肿瘤抑制基因的假设。尽管在包括乳腺癌在内的许多恶性肿瘤中都有RAR β2表达缺失的报道，但其分子机制尚不清楚。我们假设RAR β2活性的丧失可能是由多种因素引起的，包括表观遗传修饰和杂合性（LOH）的丧失。通过甲基化特异性聚合酶链反应和LOH分析，我们发现通过母子等位基因的表观遗传改变，或一个等位基因的表观遗传修饰结合剩余等位基因的遗传缺失，双等位基因失活可以完全抑制乳腺癌中RAR β2的表达。因此，大量的人类癌症可能是通过抑制基因沉默，通过表观遗传机制使两个等位基因失活而产生的。因此，染色质重塑药物可能为癌症的预防和治疗提供一种新的策略。

A growing body of evidence supports the hypotheses that retinoic acid receptor β2 (RAR β2) is a tumor suppressor gene. Although the loss of RAR β2 expression has been reported in many malignant tumors, including breast cancer, the molecular mechanism is still poorly understood. We hypothesized that loss of RAR β2 activity could result from multiple factors, including epigenetic modification and loss of heterozygosity (LOH). Using methylation-specific polymerase chain reaction and LOH analysis, we found that biallelic inactivation via epigenetic changes of both maternal and paternal alleles, or epigenetic modification of one allele combined with genetic loss of the remaining allele, could completely suppress RAR β2 expression in breast cancer. Thus, it is possible that substantial numbers of human cancers arise through suppressor gene silencing via epigenetic mechanisms that inactivate both alleles. Because of this, chromatin-remodeling drugs may provide a novel strategy for cancer prevention and treatment.