Mouse transgenic for murine oviduct-specific glycoprotein promoter-driven simian virus 40 large T-antigen: tumor formation and its hormonal regulation.

Abstract

Transgenic mice were generated in which a 2.2-kb segment of the 5'-flanking sequence of the mouse oviduct-specific glycoprotein (OGP) gene was used to drive expression of the simian virus 40 large T antigen (Tag). These mice spontaneously developed tumors in the female reproductive tract. Analysis using reverse transcriptase-polymerase chain reaction showed that the 2.2-kb OGP 5'-flanking region drove Tag mRNA expression in the oviduct, uterus, vagina, and ovary, but not in other tissues. Histological and immunohistochemical analyses revealed that the tumor cells were distributed in the oviduct, endometrium, myometrium, and vagina; and had atypical features, abnormal mitosis, and Tag expression. Ovariectomy suppressed Tag expression, and thereby, blocked tumorigenesis in the transgenic mice. Estradiol administration to ovariectomized transgenic mice led to dramatic hyperplasia of the reproductive tract tissues in association with enhanced Tag expression, both in intensity and distribution. These results demonstrated that a 2.2-kb fragment of the 5'-flanking sequence of the mouse OGP gene was capable of directing the expression of Tag and inducing tumorigenesis in female reproductive tract tissues in an estrogen-dependent manner. Estrogen response elements present in the promoter region were functional in vivo. These transgenic mice represent a unique model, since they develop tumors in the oviducts as well as in other tissues derived from the Mullerian duct.