Abstract
Germline mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose
individuals to breast and ovarian cancers. Progress in determining
the function of BRCA1 and BRCA2 suggests that they are involved in
two fundamental cellular processes: DNA damage repair and transcriptional
regulation. We evaluate current knowledge of BRCA1 and BRCA2 functions
to explain why mutations in BRCA1 and BRCA2 lead specifically to
breast and ovarian cancer. The BRCA1 and BRCA2 genes contain unusually
high densities of repetitive elements. These features of the BRCAs
genomic regions contribute to chromosomal instability of these genes.
We propose that somatic alterations of BRCA1 and BRCA2 are common
and driven by rearrangements between repetitive elements. Inherited
and somatic mutations occur in BRCA1 and BRCA2; virtually all somatic
mutations are the result of large genomic rearrangements. What are
the consequences of such large somatic mutations of BRCA1 and BRCA2
in women with or without inherited mutations? The breast and ovary
are estrogen-responsive tissues. Beginning in puberty, the breast
epithelium proliferates rapidly in response to fluctuating levels
of estrogen. We present a genetic model outlining how BRCA-deficient
cells may gain uncontrolled proliferation leading to tumor formation.
Central to this model of BRCA-mediated tumorigenesis are estrogen-mediated
proliferation of breast and ovarian epithelium and the distinctive
genomic context of the BRCA genes.
- brca2_protein
- breast_neoplasms,_genetics
- cell_division
- chromosomes,_ultrastructure
- estrogens,_metabolism
- female
- genes,_brca1,_genetics
- genetic_predisposition_to_disease
- gene_deletion
- humans
- models,_biological
- mutation
- neoplasm_proteins,_genetics
- ovarian_neoplasms,_genetics
- repetitive_sequences,_nucleic_acid
- transcription_factors,_genetics
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