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Transcriptional Regulation of BRCA1

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Annual rept. 15 Sep 1998-14 Sep 1999

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Germline mutations in BRCA1 lead to an increased risk of breast and ovarian cancer, with loss of the second, normal allele critical to tumorigenesis. It was widely presumed that the cloning and characterization of genes involved in hereditary breast cancer would lead to a better understanding of the genesis of the more common non-inherited forms of breast cancer. The relative lack of somatic mutations found in BRCA1, however, has argued against its involvement in non-inherited breast cancer. Our research specifically addresses whether large genomic rearrangements are responsible for somatic inactivation of BRCA1. We characterized the types of large germline rearrangements that occur within the BRCAl region and investigated the contribution of two large germline rearrangements to breast cancer in a population-based series of breast cancer patients. In order to determine whether BRCAl is inactivated somatically by large rearrangement of BRCA1, we analyzed 92 breast carcinomas using loss of heterozygosity analysis, Long PCR, Southern analysis, and immunohistochemistry. Although two large germline rearrangements were detected in our series, no large somatic rearrangements were identified. As previously reported BRCAl protein was reduced in the majority of breast tumors of high histologic grade. Interestingly, reduced BRCAl protein in sporadic breast carcinomas was significantly associated with loss of the most 5 BRCAl intragenic marker.

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  • Anatomy and Physiology
  • Medicine and Medical Research

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