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    Research Grants Awarded

    Identifying the immunologic signature of early stage breast cancer using the neu-transgenic mouse to model the immunogenicity of human breast cancer

    Study Section:
    Detection/Diagnosis/Prognosis

    Scientific Abstract:
    Human breast cancer is immunogenic, as evidenced by the presence of T cell infiltration in cancer and tumor antigen specific antibodies in patient sera. The immunogenicity of human breast cancer may be utilized to identify biomarkers for the early diagnosis of the disease. Of the multitude of breast cancer-associated antigens that have been identified it is unknown which ones would be useful as potential diagnostic markers. Our initial studies have demonstrated that spontaneous breast tumors in neu transgenic (neu-tg) mice, a model of human HER-2/neu (HER2) positive breast cancer, are immunogenic, similar to human breast cancer. Using serological screening of cDNA expression library (SEREX), we identified 15 tumor antigens associated with late stage tumors, and more than half of the murine tumor antigens have immunogenic human homologues. The predictive value of the mouse antigens demonstrates that this transgenic mouse model is a valuable discovery tool. Multiple tumor antigens identified in mice with advanced stage disease, as described in the Background, are proteins involved in cancer metastasis. This observation leads us to hypothesize that antigens in early stage cancer may be proteins involved in cancer initiation and the transition from pre-malignant to malignant disease, and may be useful biomarkers for early detection. Neu-tg mice can be used to model the immunogenicity of human breast cancer. The immunologic signature of early stage breast tumors, identified in neu-tg mice, will be largely homologous to human tumors and may predict novel serum biomarkers for the early detection of human breast cancer. We will utilize sera from neu-tg mice to identify a potential panel of diagnostic serum antibodies and then determine whether this panel can distinguish between tumor-bearing mice and mice that never developed tumors. In our colony of neu-tg mice, approximately 70% will develop tumor at 8-10 months of age. Baseline samples will be collected at 3 months of age, and serial serum samples will be collected every 3 weeks starting from 6 months of age. The serum samples from mice before and after they develop tumor will be studied using subtractive SEREX. We aim to identify a panel of tumor antigens whose antibodies are detected in serum before the presence of palpable tumors. The identified antibody biomarkers will be tested in an independent mouse sera sample set, in a blinded fashion, to determine if the biomarkers can be used to predict the 70% of mice that develop tumor from the 30% that do not develop tumor. Finally, we will evaluate the immunogenicity of the human homologues of the mouse tumor antigens in women with breast cancer using stored serum samples from early stage premenopausal breast cancer patients and age-matched volunteer donors derived from our specimen bank. Results generated from this study may help us predict novel serum biomarkers useful for the early detection of human breast cancer.

    Lay Abstract:
    Early detection of breast cancer leads to a much greater chance of successful treatment and more treatment choices. Despite the availability of routine screening with mammography, about 40% of breast cancers have already spread beyond the primary site by the time they are first diagnosed. Early detection by novel methods is especially important in younger pre-menopausal women, whose mammograms may be compromised by increased breast density. Human breast cancer is immunogenic, and the body?s immune system can detect and respond to cancer even at pre-malignant levels. Therefore, we propose to use serum antibodies that recognize tumor-specific proteins as biomarkers for early stage breast cancer. Serum antibodies have been shown to be effective at detecting and diagnosing cancer, and thousands of human tumor antigens have already been identified. However, the task remains to prioritize these antigens and to develop them into a rigorous test for early stage breast cancer. To do so requires well-controlled serial samples that range from pre- to post-tumor development, a situation that we can most readily obtain in an animal model. Our initial studies have demonstrated that breast tumors that develop in the neu transgenic (neu-tg) mouse, a model of human pre-menopausal estrogen receptor negative, HER-2/neu (HER2) positive breast cancer, are immunogenically similar to human breast cancer. Furthermore, the murine tumor antigen repertoire can be used to predict human tumor antigens. Therefore, we propose to use this mouse model as a discovery tool to identify new serum antibody markers for the early detection of breast cancer. In the proposed study, baseline samples will be collected at 3 months of age and serial serum samples will be collected every three weeks from neu-tg mice starting at 6 months of age. Approximately 70% of the mice will develop tumors between 8 to 10 months of age. We will first identify serum antibody markers by comparing the pre-tumor and early stage tumor sera from the mice that develop cancer using subtractive serological screening of cDNA expression library (SEREX), a high-throughput immunologic screening method. The identified antibody biomarkers will be tested in an independent mouse sera sample set, in a blinded fashion, to determine if the biomarkers can be used to predict the 70% of mice that develop tumor from the 30% that do not develop tumor. Finally, we will evaluate the immunogenicity of the human homologues of the mouse tumor antigens in women with breast cancer using stored serum samples from early stage premenopausal breast cancer patients and age-matched volunteer donors derived from our specimen bank. Results generated from this study may help us predict novel serum biomarkers useful for the early detection of human breast cancer.