Welcsh P L, Schubert E L, King M C
Department of Medicine, University of Washington, Seattle 98105, USA.
Clin Genet. 1998 Dec;54(6):447-58. doi: 10.1111/j.1399-0004.1998.tb03764.x.
A role for BRCA1 and BRCA2 in the control of genome integrity easily fits a tumor suppressor model. It is well established that mutations in DNA repair genes lead to genomic instability (138). Genomic instability may directly lead to tumorigenesis by allowing for the accumulation of mutations in key cell cycle regulators (139). The studies summarized here suggest that BRCA1, BRCA2, RAD51. and BARD1 function as a biochemical complex. This complex apparently plays a role in one or more of the DNA damage response pathways. Experimental data suggest that BRCA1 and BRCA2 function as regulators of transcription. These observations highlight some of the fundamental questions that remain to be addressed in the study of the biology of these genes. Are the DNA repair and transcriptional regulatory functions of BRCA1 and BRCA2 related? BRCA1 and BRCA2 may maintain the integrity of the genome by regulating expression of genes directly involved in this process. Alternatively, if the functions are not related, which is required for suppression of tumorigenesis? Researchers also are grappling with another paradox. If BRCA1 and BRCA2 are ubiquitously expressed, why do mutations in BRCA1 and BRCA2 lead specifically to tumors primarily of the breast and ovary, as well as a limited number of other tissues to a lesser degree? Nothing to date has been revealed that would explain how alteration of the transcriptional regulatory function and or the DNA repair function ascribed to BRCA1 and BRCA2 would result in tumor specificity as both of these functions are essential to a broad spectrum of tissues. It is possible that BRCAI and BRCA2 may regulate genes expressed only in the breast and ovary. Similarly, there may be unidentified BRCA1 and BRCA2 co-factors that are active only in the breast and ovary and, therefore, are critical to tumorigenesis. All breast cancer is genetic, although only a small fraction of cases are attributable to inherited genetic predisposition. Most breast cancer is due to genetic alterations that are specific to breast epithelial cells, many of which remain unknown. Integration of genetic approaches into research designed to elucidate biological pathways of breast cancer tumorigenesis will ultimately lead to new information critical to the development of new tools for the diagnosis and treatment of disease.
BRCA1和BRCA2在控制基因组完整性方面所起的作用很容易符合肿瘤抑制模型。众所周知，DNA修复基因的突变会导致基因组不稳定（138）。基因组不稳定可能通过使关键细胞周期调节因子中的突变积累而直接导致肿瘤发生（139）。这里总结的研究表明，BRCA1、BRCA2、RAD51和BARD1作为一种生化复合物发挥作用。这种复合物显然在一个或多个DNA损伤反应途径中起作用。实验数据表明，BRCA1和BRCA2作为转录调节因子发挥作用。这些观察结果突出了在这些基因生物学研究中仍有待解决的一些基本问题。BRCA1和BRCA2的DNA修复和转录调节功能相关吗？BRCA1和BRCA2可能通过调节直接参与这一过程的基因的表达来维持基因组的完整性。或者，如果这些功能不相关，抑制肿瘤发生需要哪一种功能？研究人员也在努力解决另一个矛盾。如果BRCA1和BRCA2普遍表达，为什么BRCA1和BRCA2的突变主要导致乳腺和卵巢肿瘤，以及在较小程度上导致少数其他组织的肿瘤？迄今为止，没有任何发现能够解释归因于BRCA1和BRCA2的转录调节功能和/或DNA修复功能的改变如何导致肿瘤特异性，因为这两种功能对广泛的组织都是必不可少的。有可能BRCA1和BRCA2可能调节仅在乳腺和卵巢中表达的基因。同样，可能存在仅在乳腺和卵巢中活跃、因此对肿瘤发生至关重要的未被识别的BRCA1和BRCA2辅助因子。所有乳腺癌都是遗传性的，尽管只有一小部分病例可归因于遗传易感性。大多数乳腺癌是由于乳腺上皮细胞特有的基因改变，其中许多仍然未知。将遗传学方法整合到旨在阐明乳腺癌肿瘤发生生物学途径的研究中，最终将产生对开发疾病诊断和治疗新工具至关重要的新信息。
