Mechanisms of Transforming Growth Factor Beta-Receptor II Loss in Breast Neoplasia

摘要

Epidemiologic studies show that most human invasive breast carcinomas arise from preexisting benign lesions. Usual hyperplasia without atypia has a two fold elevation in risk for subsequent invasive breast cancer compared with women without proliferative disease. In order to identify the women at high risk, knowledge of molecular markers of breast neoplastic progression is needed Transforming growth factor-betas are important growth suppressing factors in normal breast epithelium. and their activity is mediated by specific receptors, including transforming growth factor beta receptor II (TGFbRII). Most normal breast epithelium express high levels TGFbR II. Loss of expression of TGFbR II is related to cell proliferation and tumor progression. A recent study showed that reduced levels of TGFbR II in epithelial hyperplasia lacking atypia added an additional risk of invasive breast cancer. The molecular alterations responsible for the development and progression of proliferative breast diseases without atypia are not understood. We hypothesized that loss of TGFbR II expression in usual hyperplasia identifies a subset of women at increased risk of breast cancer. To test this hypothesis we have established a repository of African American breast biopsies from Meharry Medical College and Metropolitan Nashville General Hospital from 1960-1995 (2.255 cases). Histologically confirmed cases of usual hyperplasia without atypia lesions in African American women are selected and immunohistochemically stained for TGFbR II and Ki- 67(M1B4) to determine the loss of expression and proliferation. The percentage of positive cells in hyperplastic lesions are assessed as less than 25%, 25%-75 %, and greater than 75% for TGFbR II. A cell is considered positive if there is any nuclear staining for MlB4. In usual hyperplasia cases from the Nashville Breast Study Cohort and African American repository.