Certain human papillomavirus (HPV) types are consistently associated with squamous cell carcinoma of the female genital tract. However, these viruses are also detected in histologically normal tissues and only a small proportion of HPV-infected lesions progress to cancer which suggests that additional factors are involved in progression of this disease. In this proposal, the role of cellular oncogenes and growth factors in the pathogenesis of female genital tract cancers, particularly those of the vulva and cervix will be explored. Activated proto-oncogenes have been detected in a variety of tumor cell lines of human origin, as well as in primary human tumors. Yet whether oncogene activation is a necessary step in tumorigenesis is not known. We have analyzed 21 biopsies from 14 patients with colposcopic evidence of condyloma for amplification of the myc or Ha-ras proto- oncogenes by Southern blot hybridization. All specimens were HPV typed. Our results to date indicate that oncogene alterations a) are only detected in HPV-16, not HPV-6 or HPV-11 infected tissues, b) are not detected in premalignant lesions, and c) can occur simultaneously in two biopsies from one patient. We will expand this study to include approximately 100 cervical and vulvar intraepithelial neoplasias to determine if activation (mutation, amplification or rearrangement) of the ras, myc, and erbB/EGF receptor genes in a subset of HPV infected genital tract lesions is involved in the origin or progression of carcinoma of the female genital tract in vivo. We will also study the expression of these genes as well as that of two transforming growth factors, TGF-alpha and TGF-beta by Northern blot hybridization and in situ hybridization using antisense RNA probes. Finally, an in vitro model for papillomavirus-associated transformation using gene transfer techniques will be developed and alterations in the response of HPV-containing cervical epithelial cells to growth factors during carcinogenesis tested. These studies should give us a better understanding of the cellular response to HPV infection and help elucidate the role of human papilloma-viruses in the pathogenesis of genital tract malignancies.
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