Suzanne Tepper Newberry, M.S.

Thesis research performed under the direction of William B. Coleman

ABSTRACT
    Breast cancer is one of the most common and fatal malignancies in women.  The breast cancer susceptibility gene BRCA1 has been implicated in genetic predisposition to breast cancer, but its role in sporadic breast cancer is less clear.  To date no somatic mutations have been identified in the BRCA1 gene. Nonetheless, a third of sporadic breast tumors have reduced or abrogated expression of BRCA1 protein.  Methylation-induced epigenetic silencing of the BRCA1 gene has been identified as the cause of reduced BRCA1 protein in sporadic breast tumors.  We have found that 22% of sporadic breast tumors have reduced BRCA1 protein expression, and that reduced expression may correlate with smoking.  Cell lines that do not express or have reduced expression of BRCA1, uniformly reexpress the gene following treatment with 5-Aza-dC.  Furthermore, CpG dinucleotides 33, 1322, 1414, and 1415 of the BRCA1 promoter are important for methylation-induced epigenetic silencing of BRCA1.