Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, 3970 Reservoir Road NW, Washington, DC 20057, USA.
Funct Integr Genomics. 2012 Mar;12(1):63-79. doi: 10.1007/s10142-011-0251-2. Epub 2011 Sep 2.
The link between loss or defect in functional BRCA1 and predisposition for development of ovarian and breast cancer is well established. Germ-line mutations in BRCA1 are responsible for both hereditary breast and ovarian cancer, which is around 5-10% for all breast and 10-15% of all ovarian cancer cases. However, majority of cases of ovarian cancer are sporadic in nature. The inactivation of cellular BRCA1 due to mutations or loss of heterozygosity is one of the most commonly observed events in such cases. Complement-resistant retroviral BRCA1 vector, MFG-BRCA1, is the only approved gene therapy for ovarian cancer patients by the Federal and Drug Administration. Given the limited available information, there is a need to evaluate the effects of BRCA1 on the global gene expression pattern for better understanding the etiology of the disease. Here, we use Ingenuity Pathway Knowledge Base to examine the differential pattern of global gene expression due to stable expression of BRCA1 in the ovarian cancer cell line, SKOV3. The functional analysis detected at least five major pathways that were significantly (p < 0.05) altered. These include: cell to cell signaling and interaction, cellular function and maintenance, cellular growth and proliferation, cell cycle and DNA replication, and recombination repair. In addition, we were able to detect several biologically relevant genes that are central for various signaling networks involved in cellular homeostasis; TGF-β1, TP53, c-MYC, NF-κB and TNF-α. This report provides a comprehensive rationale for tumor suppressor function(s) of BRCA1 in ovarian carcinogenesis.
BRCA1 功能丧失或缺陷与卵巢癌和乳腺癌发病倾向之间的联系已得到充分证实。BRCA1 中的种系突变导致遗传性乳腺癌和卵巢癌，约占所有乳腺癌的 5-10%，所有卵巢癌的 10-15%。然而，大多数卵巢癌病例为散发性。在这些病例中，细胞 BRCA1 由于突变或杂合性丢失而失活是最常见的事件之一。联邦和药物管理局批准的唯一用于卵巢癌患者的基因治疗方法是互补抗性逆转录病毒 BRCA1 载体 MFG-BRCA1。鉴于可用信息有限，有必要评估 BRCA1 对全球基因表达模式的影响，以更好地了解疾病的病因。在这里，我们使用 Ingenuity Pathway Knowledge Base 来研究 BRCA1 在卵巢癌细胞系 SKOV3 中稳定表达导致的全球基因表达差异模式。功能分析检测到至少有五个主要途径发生了显著变化（p < 0.05）。这些途径包括：细胞间信号转导和相互作用、细胞功能和维持、细胞生长和增殖、细胞周期和 DNA 复制以及重组修复。此外，我们还能够检测到几个生物学上相关的基因，这些基因是涉及细胞内稳态的各种信号网络的核心；TGF-β1、TP53、c-MYC、NF-κB 和 TNF-α。本报告为 BRCA1 在卵巢癌发生中的肿瘤抑制功能提供了全面的依据。
