The Role of BRCA1 in Breast Cancer

For this article, Leslie Pray interviewed Chu-Xia Deng, senior investigator, Genetics of Development and Disease Branch of the National Institutes of Health. Data from the Web of Science (ISI, Philadelphia) show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age. X.L. Xu, Z. Weaver, S.P. Linke, C.L. Li, J. Gotay, X.W. Wang, C.C. Harris, T. Ried, C.X. Deng, "Centrosome amplification and a defective G(2)-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells," Molecular Cell, 3:389-95, March 1999. (Cited in 103 papers) Ever since researchers first linked the breast tumor suppressor gene BRCA1 to familial breast cancer1 nearly a decade ago, the gene has been a hot topic in cancer biology. Until recently, however, its actual function remained elusive. Chu-Xia Deng, senior investigator at the Genetics of Development and Disease Branch of the National Institutes of Health and the senior author on this paper, tried several years ago to study the gene's function by observing what happened when he disabled, or knocked out, BRCA1 in embryonic mouse cells. But the knockout embryos didn't survive. "We needed a mutation that would disable the gene but still give us material to work with," Deng says. That mutation, he and his colleagues discovered and wrote about, is a deletion of exon 11, the gene's largest exon, which codes for about 60 percent of the BRCA1 protein. Deleting exon 11 turns off BRCA1 without killing the cells. "Once we had a cell to work with," Deng says, "we could finally do the experiments we wanted to do." In particular, Deng and his colleagues wanted to examine the effects of dysfunctional BRCA1 on the cell cycle. Deng says that hints from work conducted in other labs suggested that the level of BRCA1 expression changes during the cell cycle and therefore could be involved with unchecked cellular proliferation in familial breast tumors. They used mouse embryonic fibroblast cells (MEFs) to examine how a disabled, exon 11-deficient BRCA1 gene would affect the two major cell cycle checkpoints, G1-S and G2-M. The G1-S checkpoint arrests cells in G1, thereby preventing damaged DNA from being duplicated, and the G2-M checkpoint prevents damaged chromosomes from segregating and entering mitosis. The researchers found that while the G1-S checkpoint remained intact, they discovered "quite surprisingly, that the mutated cells completely lost their G2-M cell-cycle checkpoint," Deng says. Also, about 25 percent of the cells had abnormal numbers of centrosomes that had formed abnormal mitotic spindles. These checkpoint and centrosome abnormalities lead to genetic instability, characterized by unequal chromosome segregation, abnormal nuclear division, and aneuploidy. Because most cancer cells are genetically unstable, the researchers report that BRCA1's effect on genomic stability provides an important molecular clue to the underlying mechanism of BRCA1-associated tumorigenesis. In a follow-up study published two months later in Nature Genetics, Deng's group engineered adult knockout mice with the same targeted exon 11 deletion to see how the mutation would affect mammary gland development.1 "We found the same abnormalities in the animal model as what we had seen previously," Deng says, indicating that mammary tumors suffer the same genomic instability that was observed in the BRCA1-deficient embryo study. The second study also included a more direct test of BRCA1's effect on tumorigenesis. Not only did the knockout mice develop mammary tumors, but tumor development accelerated dramatically in mice that had been doubly knocked out with a BRCA1 and p53 null allele. Deng says he believes that BRCA1 doesn't directly form a tumor, but rather "indirectly causes it by causing instability and increasing the mutation rates of other oncogenes and tumor suppressor genes," like p53. "BRCA1-associated tumorigenesis is quite a complex mechanism," Deng says, "and our studies provide clues as to how it happens." Deng attributes this paper's high citation standing to the topic itself. Breast cancer research is popular among scientists and has the infamous status of being a major killer. It's the most common cancer and second-leading cause of cancer mortality in women; 180,000 new cases are diagnosed yearly in the United States, and 43,000 U.S. women die annually from it. Deng expects that over the next several years, scientists will have a much better understanding of the precise function of BRCA1 and eventually might understand it well enough to direct therapy against mutant BRCA1. Deng and his research group are still studying this gene and trying to understand why p53 accelerates BRCA1-associated tumorigenesis. They are also studying the relationship between BRCA1 and estrogen signals during tumorigenesis. Leslie Pray can be contacted at lpray@nasw.org. References 1. Y. Miki et al., "A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1," Science, 266:66-71, 1994. 2. X. Xu et al., "Conditional mutation of BRCA1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour formation," Nature Genetics, 22:37-43, May 1999.

The Role of BRCA1 in Breast Cancer

Interested in reading more?

Become a Member of