Hereditary Breast Cancer Syndromes

Biological Function of BRCA1
To date, numerous studies have linked normal BRCA1 function to the cellular processes involved in transcription, apoptosis (programmed cell death), cell cycling, DNA repair, and developmental biology. The evidence supporting each of these functions for BRCA1 is summarized in the sections that follow.

Convincing evidence now exists that BRCA1 is a nuclear protein, and it is likely to play a role in altering the expression of other genes and in the response to DNA damage. Some controversy arose with the report of the presence of a granin motif in BRCA1, which is characteristic of secreted molecules normally found in the cytoplasm and membrane of cells.90 However, overwhelming evidence now suggests that BRCA1 is not secreted; and that the observations made suggesting that BRCA1 is a secreted molecule may have arisen due to a lack of specificity of the early BRCA1 antibodies.

For the most part, BRCA1 protein does not display homology to any other known motif or gene. The two exceptions are the RING finger domain at the beginning of BRCA1 and the BRCT motif at the end of the gene. The 126 base pair region of homology to a RING finger motif near the amino terminus of the protein binds zinc and is thought to be involved in protein-protein interactions.

Two novel proteins, BAP1 (BRCA1 activator protein 1) and BARD1 (BRCA1-associated RING domain protein 1), have now been identified that bind the BRCA1 RING finger. BAP1 is thought to enhance BRCA1-mediated cell growth suppression, whereas BARD1 may be involved in response to DNA damage. Further study of the function of both BARD1 and BAP1 should help define the function of BRCA1.

BRCA1 and Transcription
Evidence is mounting in support of a role for BRCA1 as a transcriptional coactivator-a protein that facilitates transcription of genes in the presence of direct transcriptional activators. First, BRCA1 has been shown to interact with two key components of the cell’s transcription machinery-the RNA polymerase holoenzyme and the transcription factor CREB binding protein.

In addition, two groups have characterized a transcriptional activation domain in the carboxy terminus of the BRCA1 protein. Finally, BRCA1 has been shown to bind p53, a critical component of response to DNA damage that is itself known to be a direct transcriptional activator. The interaction between BRCA1 and p53 has been associated with activation of p21 expression; this leads to a cell cycle pause, which may be necessary for DNA damage repair to take place. Without this pause, which could perhaps not occur if BRCA1 was absent or mutated, mutations in additional genes could accumulate, facilitating malignant transformation.

BRCA1 and Development
Wild-type BRCA1 appears to play a critical role in both mouse and human development. The first studies of the role of BRCA1 in development were performed by in situ hybridization of mouse embryos and indicated that BRCA1 was widely expressed in many developing tissues. These investigations also demonstrated that BRCA1 was highly expressed in the mouse mammary gland during development and pregnancy.

Proof that BRCA1 is necessary for normal mouse development was provided by the derivation of four BRCA1 “knockout” mouse strains, each of which died in early embryonic development. The mechanisms by which BRCA1 exerts an effect on mouse development and its role in human development remain unclear; however, this pathway provides another means of defining BRCA1 function.

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