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    Awarded Grants
    Characterization of Immunosuppressive Properties Induced by Eukaryotic Vector-Mediated Expression of HERV Genes Derived from Human Breast Cancer Cells

    Scientific Abstract:
    HERVs comprise up to 80% of the human genome. In general, these HERVs are mostly noninfectious, replication-defective, retroviral remnants transmitted as stable Mendellian genes. HERV-K is transcriptionally active in several human cancer tissues as well as tumor cell lines, most notably the human breast cancer cell line T47D and breast cancer tissues, as determined by our group. Recently, our real-time RT-PCR data showed that enhanced expression of HERV-K env gene in breast cancer cells may be specifically associated with estradiol and progesterone activation and breast cancer development. Both types of HERV-K env transcripts were capable of being spliced in subgenomic env transcripts, and various spliced donor and acceptor sites were detected in breast cancer tissue. Two spliced HERV-K env subhenomic transcripts, central open reading frame (cORF) and np9, have been associated with tumorigenesis by other groups. HERV proteins appear to be immunogenic in patients with cancer. An antibody response to the gag and env proteins of HERV-K has been identified in patients with seminoma and germ cell tumors (85%), but not in normal controls, suggesting synthesis of these proteins in vivo, and that immune reaction against HERV-K can be specific for defined ERV protein. The antibody titers of the patients showed a decrease with time after the patients received antitumor treatment or tumor removal. We detected anti-HERV env protein antibodies in sera of some breast cancer patients using various HERV purified env proteins. In a mouse model system, tumor cells expressing a retroviral envelope protein escaped immune rejection and resulted in tumor growth in vivo. Furthermore, two groups demonstrated that ERV9 and HERV-H env region encode TM proteins with immunosuppressive activity. Their results emphasize the close relationship between endogenous and infectious retroviruses, and might be important in relation to the process of tumor progression in humans. We hypothesize that these novel HERV genes play a role(s) in the immune response to breast tumors, and lead to enhanced ability of tumor cells to escape host immune rejection in breast cancer cells. The aim of these studies is to investigate expression of HERV in breast tumor tissues, and to evaluate whether HERV expression is specifically associated with escape from host immune surveillance and the subsequent tumor progression. A transgenic model of tumor development will be used to test whether or not there is an effect on the host immune system. We hypothesize that these HERV env genes and their protein products may induce tumor formation or play a role(s) in tumorigenicity due to their immunosuppressive properties.

    Lay Abstract:
    One of the major hurdles to successful immunodiagnosis and immunotherapy of human cancer is the paucity of human tumor specific antigens. This application proposes that the protein products of human endogenous retroviruses (HERVs) may represent a novel family of breast tumor specific antigens. These retroviral genes reside in our genetic makeup (germ lines) and are usually not expressed in normal tissues but often are expressed in tumor tissues. We propose to identify and characterize the HERV proteins or pieces of proteins expressed uniquely in breast cancer tissues as potential tumor associated antigens. A mouse model of tumor development will be used to test whether or not there is an effect on the host immune system. Our preliminary studies provide evidence that some HERVs are present and expressed in breast cancer. Our data demonstrated that enhanced expression of HERV-K env gene in breast cancer cells may be specifically associated with hormone stimulation and breast cancer development. Other groups have demonstrated that tumor cells expressing a retroviral envelope protein escaped immune rejection and resulted in tumor growth in vivo. In addition, two spliced retroviral proteins, central open reading frame (cORF) and np9, have been associated with tumor growth. These results emphasize the close relationship between endogenous and infectious retroviruses, and might be important in relation to the process of tumor progression in humans. We hypothesize that these HERV env genes and their protein products that may induce tumor formation or play a role(s) in tumorigenicity due to their immunosuppressive properties.