A Cohort Study of the Relationship Between c-erbB-2 and Cyclin D1 Overexpression, p53 Mutation and/or Protein Accumulation, and Risk of Progression from Benign Breast Disease to Breast Cancer; and Creation of a Bank of Benign Breast Tissue.

Abstract : In a case control study, nested within a cohort of 4,888 women with benign breast disease, we demonstrated that p53 protein accumulation detected by immunohistochemistry was associated with a two-fold increase in risk to develop breast cancer. The purpose of this project is: 1) collect paraffm-embedded benign breast tissue from the remaining 4,336 cohort members who were not part of the case-control study. (2) to enlarge the completed case-control study of p53 with an additional 63 cases (and 5 matched controls per case) and examine the biopsies from these subjects for evidence of c-erbB-2 overexpression and p53 protein accumulation. As well, we will examine the tissue for the presence of p53 mutations in this group and (3) examine whether cyclin Dl amplification and/or protein overexpression is a molecular marker of risk of progression from BBD to breast cancer. The collection of paraffin blocks is ongoing. We have analyzed all the p53 immunopositive breast tissues and 15 subjects whose breast tissue did not show pS3 protein accumulation. p53 sequence changes occurred in 59.2% (16/27) of p53 immunopositive tissues and of these 33% (9/27) were p53 mutations. Four (26.7%) of the immunonegative tissues showed gene alterations of which one was a mutation. The existing case-control group was examined for cyclin Dl changes. Twelve cases and 29 controls showed cyclin Dl amplification. After adjustment for confounding there was a statistically non-significant 40% increase in risk of breast cancer in association with cyclin Dl amplification. Cyclin Dl overexpression was seen in 75 samples of benign breast disease (15 cases and 60 controls). The presence of cyclin Dl overexpression was not associated with increased risk of developing breast cancer (unadjusted odds ratio 1.07, 95% confidence intervals 0.56-2.03).