SQUAMOUS EPITHELIAL HYPERPLASIA AND CARCINOMA IN MICE TRANSGENIC FOR THE HUMAN PAPILLOMAVIRUS TYPE-16 E7 ONCOGENE

The human papillomavirus type 16 (HPV-16) genome is commonly present i n human cervical carcinoma, in which a subset of the viral genes, E6 a nd E7, are expressed. The HPV-16 E6 and E7 gene products can associate with and inactivate the tumor suppressor proteins p53 and Rb (the ret inoblastoma susceptibility gene product), and in tissue culture cells, these viral genes display oncogenic properties. These findings have l ed to the hypothesis that E6 and E7 contribute to cervical carcinogene sis. This hypothesis has recently been tested by using transgenic mice as an animal model. HPV-16 E6 and E7 together were found to induce ca ncers in multiple tissues in which they were expressed, including squa mous cell carcinoma, the cancer type most commonly associated with HPV -16 in the human cervix, We have extended these studies to investigate the in vivo activities of HPV-16 E7 when expressed in squamous epithe lia of transgenic mice. Grossly, E7 transgenic mice had multiple pheno types, including wrinkled skin that was apparent prior to the appearan ce of hair on neonates, thickened ears, and loss of hair in adults. In lines of mice expressing higher levels of E7, we observed stunted gro wth and mortality at an early age, potentially caused by an incapacity to feed. Histological analysis demonstrated that E7 causes epidermal hyperplasia in multiple transgenic lineages with high penetrance. This epithelial hyperplasia was characterized by an expansion of the proli ferating compartment and an expansion of the keratin 10-positive layer of cells and was associated with hyperkeratosis. Hyperplasia was foun d at multiple sites in the animals in addition to the skin, including the mouth palate, esophagus, forestomach, and exocervix, In multiple t ransgenic lineages, adult animals developed skin tumors late in life w ith low penetrance. These tumors arose from the squamous epithelia and from sebaceous glands and were characterized histologically to be hig hly differentiated, locally invasive, and aggressive in their growth p roperties. On the basis of these phenotypes, we conclude that HPV-16 E 7 can alter epithelial cell growth parameters sufficiently to potentia te tumorigenesis in mice.