Roles of BRCA1 transcription target genes in tumorigenesis and aging

最近，我们已经表明，小鼠，这是一个有针对性的删除全长Brca 1纯合子，和杂合子的p53无效突变（Brca 111/11 p53 +/）表现出过早衰老的特征是寿命缩短，减少体内脂肪沉积，骨质疏松症，皮肤萎缩，伤口愈合减少。当剩余的野生型（WT）p53等位基因丢失时，Brca 111/11 p53 +/小鼠的肿瘤发生也会增加。这些缺陷背后的分子机制尚不清楚。使用DNA微阵列和候选方法，我们已经确定了超过100个基因，在BRCA 1突变体和对照细胞中差异表达。基于突变小鼠和细胞的表型分析和验证这些基因可能允许鉴定与肿瘤发生相关的最早变化，以及用于早期诊断乳腺肿瘤的标记物。 衰老在人类中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退化。多种环境和/或遗传相关因素，包括Sir 2和胰岛素样生长因子-1（IGF-I）信号传导，已与各种衰老症状相关。在过去的一年里，我们一直专注于BRCA 1和IGF-1信号通路之间的相互作用，肿瘤发生和衰老。我们的数据表明，在多个实验系统中，包括BRCA 1缺陷小鼠，原发性乳腺肿瘤和培养的人类细胞，Brca 1缺陷导致几个IGF信号传导轴成员（即IGF-1，IGF受体-1和IRS-1）的表达增加。此外，我们提供的证据表明，激活IGF信号BRCA 1缺陷也可以发生在一个p53独立的方式。我们的数据表明，BRCA 1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的表观遗传修饰相关的转录抑制染色质构型。我们进一步表明，BRCA 1缺陷型乳腺肿瘤细胞表现出高水平的IRS-1，使用RNA干扰对IRS-1的急性抑制显著抑制了这些细胞的生长。这些观察结果为理解基本和治疗性BRCA 1相关肿瘤发生和衰老提供了分子见解。

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.