TRAF-4 EXPRESSION IN EPITHELIAL PROGENITOR CELLS - ANALYSIS IN NORMALADULT, FETAL, AND TUMOR-TISSUES

TRAF-4 was discovered because of its expression in breast cancers and is a member of the tumor necrosis factor (TNF) receptor-associated fac tor (TRAF) family of putative signal-transducing proteins. In vitro bi nding assays demonstrated that TRAF-4 interacts with the cytosolic dom ain of the lymphotoxin-beta receptor (LT beta R) and weakly with the p 75 nerve growth factor receptor (NGFR) but not with TNFR1, TNFR2, Fas, or CD40, Immunofluorescence analysis of TRAF-4 in transfected cells d emonstrated localization to cytosol but not nucleus. Immunohistochemic al assays of normal human adult tissues revealed prominent cytosolic i mmunostaining in thymic epithelial cells and lymph node dendritic cell s but not in lymphocytes or thymocytes, paralleling the reported patte rns of LT beta R expression. The basal cell layer of most epithelia in the body was very strongly TRAF-4 immunopositive, including epidermis , nasopharynx, respiratory tract, salivary gland, and esophagus, Simil ar findings were obtained in 12- to 18-week human fetal tissue, indica ting a highly restricted pattern of expression even during development . In the mammary gland, epithelial cells of the terminal ducts were st rongly TRAF-4 immunopositive whereas myoepithelial cells and most of t he mammary epithelial cells lining the extralobular ducts were TRAF-4 immunonegative, Of 84 primary breast cancers evaluated, only 7 express ed TRAF-4, Ductal carcinoma in situ (DCIS) lesions were uniformly TRAF -4 immunonegative (n = 21), In the prostate, the basal cells were stro ngly immunostained for TRAF-4, whereas the secretory epithelial cells were TRAF-4 negative. Basal cells in prostate hypertrophy (n = 6) and prostatic intraepithelial neoplasia (PIN; n = 6) were strongly TRAF-4 positive, but none of the 32 primary and 16 metastatic prostate cancer specimens examined contained TRAF-4-positive malignant cells. Althoug h also expressed ire some types of mesenchymal cells, these findings s uggest that TRAF-4 is a marker of normal epithelial stem cells, the ex pression of which often ceases on differentiation and malignant transf ormation.