Roles of BRCA1 transcription target genes in tumorigenesis and aging

最近，我们发现Brca1全长基因的纯合子和p53缺失突变（Brca111/11p53+/）的杂合子小鼠表现出过早衰老，其特征是寿命缩短、体脂沉积减少、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+/小鼠也会增加肿瘤发生。这些缺陷的分子机制尚不清楚。利用DNA微阵列和候选方法，我们已经确定了100多个在BRCA1突变体和对照细胞中差异表达的基因。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。

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.