尽管在多年前已经知道，“乳腺癌基因”BRCA1的缺陷能够增加人患乳腺癌的风险，但是它如何导致肿瘤生长却仍然是个谜。
在10月15日的《癌症研究》（Cancer Research）杂志上，来自美国芝加哥大学和日本京都大学的研究人员的新研究揭示出一种正常情况下修复受损DNA的机制可能在BRCA1功能异常时导致乳腺癌的发生。
他们的新发现使得对正常BRCA1基因如何抑制肿瘤的生长以及遗传稳定性本质有了更进一步的了解。
领导这项研究的Douglas Bishop和同事发现，因缺少BRCA1导致的生长缓慢可能通过增加DNA修复蛋白RAD51而得到补偿。
RAD51与同源重组有关，而同源重组则是细胞修复受损DNA的一种常用方法。在同源重组中，生物体利用未断裂的染色体拷贝作为模板来修复断裂的染色体。
BRCA1本身能通过重组来促进DNA修复，并且通常的观点认为BRCA1的丧失是由于DNA修复的失败而导致肿瘤发生的。这项新的研究则挑战了这个经典理论。
Bishop指出，BRCA1缺陷本身可能并不会导致肿瘤的发生，但是试图通过增加RAD51水平来补偿修复过程中的BRCA1缺陷的细胞则可能比普通细胞的遗传稳定性要差一些，因此更容易形成肿瘤。
利用一个公共数据库，Bishop和同事分析了117个原发性乳腺肿瘤的基因组数据，并发现其与同源重组有关的基因的RNA水平增加了。他们发现，RAD51和另外两个关键的附属因子的基因的RNA水平在BRCA1缺陷肿瘤中明显高于与BRCA1突变无关的乳腺肿瘤样本。
原文出处：
Public release date: 15-Oct-2007
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Contact: John Easton
john.easton@uchospitals.edu
773-702-6241
University of Chicago Medical Center
Enhanced DNA-repair mechanism can cause breast cancer
Although defects in the "breast cancer gene," BRCA1, have been known for years to increase the risk for breast cancer, exactly how it can lead to tumor growth has remained a mystery. In the October 15, 2007, issue of the journal Cancer Research, scientists from the University of Chicago and Kyoto University, Japan, suggest that a mechanism that normally repairs damaged DNA may function abnormally in BRCA1 carriers leading to one type of poor-prognosis breast cancer.
Their findings provide insight into how the normal BRCA1 gene suppresses the growth of tumors as well as the nature of the genetic instability that leads to cancer when BRCA1 is defective.
"If you take a normal, healthy cell and get rid of BRCA1, you end up with an unhealthy, slow-growing cell," said Douglas Bishop, PhD, associate professor of radiation and cellular oncology at Chicago and principal investigator of the study. "That抯 a bit of a paradox, because loss of BRCA1 also causes tumors and tumor formation is not normally associated with poor cell growth."
Bishop and colleagues found that the slow growth caused by loss of BRCA1 could be compensated for by increasing the amount of the DNA repair protein RAD51.
RAD51 is involved in homologous recombination, a method used by cells to repair damaged DNA. In homologous recombination, organisms heal broken chromosomes using an unbroken chromosome copy as a template.
BRCA1 itself promotes DNA repair through recombination and the conventional view is that loss of BRCA1 causes tumors because DNA repair fails. The new work from Bishop and colleagues challenges this view.
"BRCA1-deficiency by itself would probably not cause a tumor," Bishop said, "but cells that manage to compensate for the BRCA1 defect in repair by ramping up RAD51 levels are likely to be less genetically stable than normal cells and therefore more prone to form tumors."
Using a public database, Bishop and colleagues examined genomic data from 117 primary breast tumors for evidence of elevated levels of RNAs for genes involved in homologous recombination. They found that the level of RNA for three genes -- RAD51 and two of its key accessory factors -- was significantly higher in BRCA1-deficient tumors compared with breast tumors that were not associated with BRCA1 mutations.
"High levels of RAD51 may help cells that lack BRCA1 overcome the defects in recombination caused by loss of BRCA1," Bishop said, "but the recombination that occurs in this situation may be abnormal and may actually cause mutations which in turn lead to the development of a tumor."
When the researchers took normal, healthy cells in culture and disabled the BRCA1 gene, the cells survived, but grew slowly and were unable to repair DNA damage normally. When Bishop and his coworkers increased the amount of RAD51 in these cells, however, the ability of cells to repair DNA damage was restored and the mutated cells grew more quickly.
In the future "it will be interesting to determine whether high levels of RAD51 can predict tumor prognosis," said Bishop. "Its also possible that tumor cells with high levels of RAD51 are particularly dependent on that gene for survival and therefore sensitive to drugs that target RAD51"
The National Cancer Institute funded the work done at the University of Chicago and the CREST Research Project, Japan Science and Technology, Kyoto funded the effort in Japan. Additional authors of the paper include Richard D. Martin, Brian J. Orelli and Andy J. Minn from Chicago, and Mitsuyoshi Yamazoe and Shunichi Takeda of Kyoto University.
