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From refs. 91-97,144.

From refs. 91-97,144.

development of cancer requires alteration of the second allele. However, unlike classical tumor suppressor genes, no disease-associated dominant mutations in BRCA1 or BRCA2 have been found in sporadic ovarian or breast cancers (104). These findings suggest a more complex paradigm of BRCA function. The model of Kinzler and Vogelstein (105) proposes that some genes act as "gatekeepers"—their mutation results in lifting of normal controls on cell division or apoptosis, allowing accelerated growth of cancer cells. In contrast, a "caretaker" gene may indirectly cause cancer when loss-of-function results in genomic instability. Cells deficient in the murine BRCA2 analog accumulate spontaneous abnormalities in chromosome structure indicative of defective mitotic recombination (106). In vitro, similar aberrations are seen in murine cells deficient in BRCA1 and in human cancer cells deficient in BRCA1 or BRCA2 (107-109). These findings suggest that the BRCA genes are necessary for maintaining genomic integrity. Accordingly, BRCA genes may function as "caretakers." In patients with germline mutations in the BRCA, genes might have a predisposition to tumorigenesis, the loss of additional genes that function in concert with loss of BRCA function might be required for development of actual cancer.

Two principal methods of double-strand DNA break repair that exist are homologous recombination and nonhomologous end joining. Homologous recombination utilizes a complex of multiple proteins to allow strand exchange and correction in a potentially error-free process. Homologous recombination is also required to restart stalled replication forks (110). In contrast, nonhomologous end joining utilizes a sequence of various proteins to ligate broken ends, a process that is tolerant of nucleotide alterations at the site of ligation.

A key function of the BRCA genes appears to be maintenance of genomic integrity through homologous recombination. Although BRCA1 has been implicated in a broad variety of cellular pathways, including DNA replication, repair of single- and doublestrand DNA breaks, cell-cycle control, apoptosis, transcription, chromatin remodeling, and protein ubiquitination, BRCA2 is only known for its function to assist in DNA repair through regulation of RAD51. The interaction of the BRCA2 and RAD51 proteins is necessary to allow RAD51 to facilitate homologous recombination DNA repair (111-113). In murine models, BRCA1 deficient embryonic stem cells have been noted to display decreased homology-directed DNA repair, which can be reversed with restoration of BRCA1 function (114,115). Although, both BRCA1 and BRCA2 proteins participate in aggregates of repair proteins in association with RAD51 in the nuclei of cells exposed to ionizing radiation, BRCA2 appears to play the more critical role. BRCA2 appears to directly control RAD51, whereas BRCA1 plays a regulatory role on both (104).

Human cells with mutated BRCA1 have also been shown to have a defect in S phase arrest in response to ionizing radiation (116,117). This defect allows mutated cells to progress through the cell cycle. BRCA1 deficient cells have also been shown to exhibit a cell-cycle checkpoint defect at G2/M (116,118,119). A particular mutation in BRCA1 has been identified in which the G2/M cell-cycle checkpoint is defective, but cells are still sensitive to radiation-induced damage (120). This leads to the conclusion that both defective DNA repair and faulty cell-cycle checkpoints collaborate in BRCA mutant cells to produce chromosomal abnormalities.

Impaired BRCA1 or BRCA2 function may promote tumorigenesis through impaired homologous recombination in cooperation with other key cellular processes. Defects in homologous recombination might lead to an error-prone process or shunting of repair into a nonhomologous end joining pathway, which is inherently error-prone. However, despite progress in elucidating the complex functions of BRCA1 and BRCA2, it remains unclear why mutation related cancer susceptibility is manifested in only specific tissues, such as breast and ovary. Proliferation of breast and ovarian epithelium may engender higher levels of DNA damage. Alternatively, BRCA deficiency might make breast or ovarian cells more sensitive to mutagens, such as estrogen metabolites. A third hypothesis is that loss of a second BRCA allele may be more likely in tissues, such as breast and ovary, where periods of increased proliferation alternate with prolonged periods of quiescence (when BRCA function may be unnecessary). Thus, leading to accumulation of cells lacking both normal BRCA alleles.

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