Abstract 4328: Beta-catenin accelerates human papillomavirus type16 -E7 mediated cervical carcinogenesis in transgenic mice

Human papilloma virus (HPV) is the principal etiological agent of cervical cancer in women and its DNA is present and expressed in virtually all cervical cancers. Exposure to the high-risk HPV types is not sufficient for tumor development. Approximately 80% of women will be infected with HPV in their lifetime, however only a small percentage of infected women develop cervical cancer. It is unknown who among the millions of women infected with HPV will go on to develop cervical cancer. Therefore, it remains critical to discover additional cellular changes that lead to malignant transformation. The persistence of viral infection is one critical factor in the predisposition to cancer, presumably providing genetic instability that leads to additional genetic/epigenetic changes. Our earlier work using an in vitro model indicated that activation of the canonical Wnt pathway in HPV-positive epithelial cells was sufficient to induce anchorage independent growth. Therefore, we hypothesized that constitutive activation of the Wnt pathway might function as a second hit. To address this possibility, we generated two new double transgenic (DT) mouse models. The first model, K14-HPV16/ΔN87βcat is established by crossing K14-ΔN87βcat mice with K14-HPV16 mice. These mice express wild type HPV16 early region oncoproteins including E6 and E7 and constitutively active -catenin protein in cervical epithelia under the control of tissue specific K14 promoter. The second model, K14-E7/ΔN87βcat mice were generated by crossing K14-ΔN87cat cat mice with K14-E7 mice and they express only the E7 oncoprotein and constitutively active -catenin under the same K14 promoter. All the transgenic animals in both crosses were maintained as heterozygotes. Within the K14-HPV16/ΔN87βcat model, we did not observe any cervical pathology in the wild type and K14-ΔN87βcat mice, whereas we observed CINIII in 26.7% of K14-HPV16 animals and CINIII and invasive tumors in 30% of the double transgenic animals at an average of 6 months of age. Within the K14-E7/ΔN87βcat model, wild type animals did not develop any cervical pathology. Invasive cervical cancer was observed in 10.5% of the animals expressing activated β-catenin and in 50% of the animals expressing HPV16-E7 oncogene. In double transgenic animals, expression of β-catenin and the HPV16-E7 oncogene induced invasive cervical cancer at an average age of 6 months in 93.75% of the cases. In summary, our data support the hypothesis that activation of