The objective of the experiments described in this proposal is to dissect the molecular mechanisms which affect the developmental regulation of expression of the endogenous murine retrovirus, mouse mammary tumor Virus (MTV) and limit the induction of mammary carcinomas by this virus to the mammary gland. An additional goal is to achieve an understanding of the genetic factors that determine whether mice are susceptible to MTV-induced mammary tumors and the role of the immune system in this process. To achieve these goals, a combination of molecular cloning techniques, tissue culture transfection studies and transgenic mice will be used to characterize the DNA sequences within the long terminal repeat (LTR) of MTV that direct expression of the virus to the mammary gland. Additionally, the transcription factors that Interact with these DNA sequences will be cloned and used to study expression of these factors in the developing mammary gland of different mouse strains and in mammary tumors. Lastly, the role of the MTV LTR open reading frame (ORF) protein, which influences the T cell repertoire in mice, will be assessed, In both the virus life cycle and in the susceptibility of different strains of mice to MTV-induced carcinomas. The experiments outlined in this proposal will allow us to begin to dissect the contributions of genetic background to the tumorigenic process initiated by MTV and the role of the immune system in responding to viral infection and tumorigenesis. By extension, these experiments will also increase our understanding of the role of these different components in human breast cancer.
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