Between 5-10% of primate and rodent genomes consist of families of repetitive DNA elements of which retroviruses contribute > 15,000 copies. Mobility of endogenous retroviruses has occurred naturally, but neither the mechanisms inducing movement, the extent of movement, nor the genetic side effects (with minor exception) of movement are known. The present proposal will attempt to address these issues with respect to retrotransposition in the Syrian hamster model for androgen-estrogen induced leiomyosarcomas for four reasons: First, Syrian hamsters are genetically similar; second, they exhibit 100% incidence in leiomyosarcoma induction; third, many retroviral LTR's contain hormone response elements that upregulate transcription; fourth, retroviral gene expression has been documented in tumors during the induction process. This highly reproducible hormonal carcinogenesis model presents us with the opportunity to examine the extent of retrotransposition in vivo and because of the unique vectors allows us to select for new integration sites and flanking genomic DNA which may be causally linked to the cancer process. There are four specific aims addressing these interests. SPECIFIC AIM 1 is to clone a number of the more commonly expressed retroviruses expected to have the highest potential for retrotransposition. After characterization these proviruses will be engineered to contain neoGST3 genes and used to create transgenic animals. SPECIFIC AIM 2 is to develop the techniques for creating transgenic hamsters. SPECIFIC AIM 3 is devoted to creating and breeding transgenic animals, carrying out hormonal carcinogenesis protocols, and analyzing retrotransposition. SPECIFIC AIM 4 is to clone genomic DNA flanking sites of retrotransposition and characterize flanking DNA particularly as to its role in cancer. This proposal may have great relevance to cancers occurring in human endocrine target tissues such as the ovary, breast, and prostate because of the presence of > 15,000 largely uncharacterized human retroviral sequences.
NIH ExPorter
NIH ExPorter