Roles of BRCA1 transcription target genes in tumorigenesis and aging

最近，我们发现，靶向缺失全长BRCA1纯合子和杂合子P53零突变(Brca111/11P53+/)的小鼠表现出过早衰老的特征，特征是寿命缩短、体内脂肪沉积减少、骨质疏松、皮肤萎缩和伤口愈合减少。当剩余的野生型(WT)P53等位基因丢失时，Brca111/11P53+/小鼠的肿瘤发生率也会增加。这些缺陷背后的分子机制尚不清楚。利用DNA微阵列和候选方法，我们已经鉴定了100多个在BRCA1突变细胞和对照细胞中差异表达的基因。根据突变小鼠和细胞的表型分析和验证这些基因，可能会识别与肿瘤发生相关的最早变化，以及早期诊断乳腺肿瘤的标记。 在人类中，衰老被定义为与年龄相关的生物体生存和生育所必需的生理功能的恶化。多种环境和/或遗传相关因素，包括Sir2和胰岛素样生长因子-1(IGF-I)信号，与各种衰老症状有关。在过去的一年里，我们专注于BRCA1和IGF-1信号通路之间的相互作用，以促进肿瘤的发生和衰老。我们的数据表明，BRCA1缺乏导致多个实验系统中IGF信号轴成员(即IGF-1、IGF受体-1和IRS-1)的表达增加，包括BRCA1缺陷小鼠、原发乳腺肿瘤和培养的人类细胞。此外，我们提供的证据表明，BRCA1缺乏对IGF信号的激活也可以以一种不依赖于p53的方式发生。我们的数据表明，BRCA1与IRS-1启动子相互作用，并抑制其活性，这与组蛋白H3和组蛋白H4对转录抑制染色质配置的表观遗传修饰有关。我们进一步表明BRCA1缺陷的乳腺肿瘤细胞表现出高水平的IRS-1，并且使用RNA干扰急性抑制IRS-1显著地抑制了这些细胞的生长。这些观察为理解基础和治疗性BRCA1相关的肿瘤发生和衰老提供了分子洞察力。

Recently, we have shown that mice, which are homozygous for a targeted deletion of the full-length Brca1, and heterozygous for p53-null mutation (Brca111/11p53+/) exhibit premature aging characterized by decreased life span, reduced body fat deposition, osteoporosis, skin atrophy, and decreased wound healing. The Brca111/11p53+/ mice also suffer increased tumorigenesis when the remaining wild-type (WT) p53 allele is lost. The molecular mechanisms underlying these defects are not clear. Using DNA microarray and candidate approaches, we have identified over 100 genes that are differentially expressed in BRCA1 mutant and control cells. Analyzing and validating these genes based on phenotypes of mutant mice and cells may allow the identification of earliest changes associated with tumorigenesis, and markers for early diagnosis of mammary tumors. Aging has been defined in humans as the age-related deterioration of physiologic functions necessary for the survival and fertility of an organism. Multiple environmental- and/or genetic-related factors, including, Sir2, and insulin-like growth factor-1 (IGF-I) signaling, have been associated with various aging symptoms. In the past year, we have focused on interactions between BRCA1 and the IGF-1 signaling pathway for tumorigenesis and aging. Our data indicate that Brca1 deficiency leads to increased expression of several IGF signaling axis members (i.e. IGF-1, IGF receptor-1, and IRS-1) in multiple experimental systems, including BRCA1-deficient mice, primary mammary tumors, and cultured human cells. Furthermore, we provide evidence that activation of IGF signaling by BRCA1 deficiency can also occur in a p53-independent fashion. Our data indicate that BRCA1 interacts with the IRS-1 promoter and inhibits its activity that is associated with epigenetic modification of histone H3 and histone H4 to a transcriptional repression chromatin configuration. We further show that BRCA1-deficient mammary tumor cells exhibit high levels of IRS-1, and acute suppression of Irs-1 using RNA interference significantly inhibits growth of these cells. Those observations provide a molecular insight in understanding both fundamental and therapeutic BRCA1-associated tumorigenesis and aging.