THE UTEROGLOBIN PROMOTER TARGETS EXPRESSION OF THE SV40 T-ANTIGEN TO A VARIETY OF SECRETORY EPITHELIAL-CELLS IN TRANSGENIC MICE

Adenocarcinomas derived from the lining epithelia of various organs ar e the most common malignant tumors in human pathology and about 50% ar e hormone dependent. The tissue-specific and hormally regulated expres sion of the rabbit uteroglobin gene is secretory epithelial cells coul d provide a means of establishing in vivo models for a variety of huma n tumors originating from such tissues. We have generated trangenic mi ce inheriting a hybrid gene containing 4.7 kb of the rabbit uteroglobi n 5'-flanking sequences fused to the SV40 T antigen encoding region. A ll transgenic founders examined exhibited bronchio-alveolar adenocarci nomas, probably due to expression of the transgene in Clara cells. Mos t founders also developed tumors of the submandibular salivary gland, and adenocarcinomas of the stomach. Adenocarcinomas and dysplasias in epithelial cells of the male and female genital tract were found in si ngle founders. Immunohistochemical analysis showed that T antigen expr ession interfered with stable maintenance of the differentiated phenot ype as documented by expression of the endogenous uteroglobin gene. On e founder gave rise to a mouse Line, UT7.1. Transgenic descendants of UT7.1 developed lung adenocarcinomas and, depending on the genetic bac kground, exhibited tumors of the stomach, the salivery gland and the p ancreas. Sporadically male descendants developed prostatic adenocarcin oma whereas females developed dysplasias and adenocarcinomas of the ut erus and the oviduct. Thus, the UT7.1 mouse line could be a useful mod el for several epithelial neoplasias.