Epithelial ovarian cancer is the most lethal gynecological
malignancy among US women. The etiology of this disease, although poorly understood, may involve the ovarian surface epithelium or the epithelium of the fallopian tube fimbriae as the progenitor cell. Disruptions in the
transforming growth factor beta (TGFβ) pathway and p53 are frequently found in
chemotherapy-resistant serous ovarian
tumors. Transgenic mice expressing a dominant negative form of Smad2 (Smad2DN), a downstream
transcription factor of the TGFβ signaling pathway, targeted to tissues of the reproductive tract were created on a FVB background. These mice developed epithelium-lined inclusion
cysts, a potential precursor lesion to
ovarian cancer, which morphologically resembled oviductal epithelium but exhibited
protein expression more closely resembling the ovarian surface epithelium. An additional genetic "hit" of p53 deletion was predicted to result in ovarian
tumors. Tissue specific deletion of p53 in the ovaries and oviducts alone was attempted through intrabursal or intraoviductal injection of
Cre-recombinase expressing adenovirus (AdCreGFP) into p53 (flox/flox) mice. Ovarian bursal
cysts were detected in some mice 6 months after intrabursal injection. No pathological abnormalities were detected in mice with intraoviductal
injections, which may be related to decreased infectivity of the oviductal epithelium with adenovirus as compared to the ovarian surface epithelium. Bitransgenic mice, expressing both the Smad2DN transgene and p53 (flox/flox), were then exposed to AdCreGFP in the bursa and oviductal lumen. These mice did not develop any additional phenotypes. Exposure to AdCreGFP is not an effective methodology for conditional deletion of floxed genes in oviductal epithelium and tissue specific promoters should be employed in future mouse models of the disease. In addition, a novel phenotype was observed in mice with high expression of the Smad2DN transgene as validated through qPCR analysis, characterized by
teratoma-like lesions implicating Smad signaling in
teratoma development.