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    Research Grants Awarded

    Humanized Mouse Model For Analysis Of Human Breast Cancer Xenotransplants

    Grant Mechanism:
    Postdoctoral Fellowships

    Scientific Abstract:
    Breast cancer is the most common cancer in women in the U.S. There has been dramatic improvement of the breast cancer treatment in the past few decades. In recent years, breast cancer research in the laboratory has identified many promising treatment targets due to greater understanding of the molecular mechanisms involved in breast cancer initiation and progression. To translate these findings from laboratory research to clinical care, the candidate therapeutic drugs have to undergo the preclinical evaluation in animal models. In vivo tests for drug screening and evaluation are usually carried out on mice using xenografts of established cancer cell lines or human tumors. However, such testing does not often yield results accordant with the human trials, which may be due to the failure of mouse models to adequately represent the human physiological conditions as the host for the xenotransplants. This is particularly true for breast cancer. Endocrine hormones have been implicated in a number of ways in breast tumor growth and progression. Among the major hormones involved, estrogen and progesterone are steroid hormones which work across species, while the two peptide hormones prolactin (PRL) and growth hormone (GH) have structurally diverged between mice and human. Our hypothesis is that hGH and hPRL in circulation are important for modeling breast cancer xenograft in vivo. In the proposed study, first, we are going to character the efficacy of mouse GH (mGH) and human GH (hGH) on breast cancer cell lines in vivo and in vitro. Then, we are to characterize the efficacy of mouse GH (mGH) and human GH (hGH) on benign and malignant human breast tissues taken directly from patients. To overcome the inability of mGH and mPRL to activate prolactin and GH receptors in human breast cancer, we will generate mice that express hGH instead of mGH and cross this new mouse into a parallel mouse line that we already have established that expresses physiological levels of human prolactin instead of mouse prolactin. We are going to test this new hGH/hPRL mouse model as a recipient of human breast cancer xenotransplants. By comparing the growth and response of the human breast cancer xenotranplants in hGH/hPRL mice with the wildtype mice, we will get valuable information about the GH/PRL involvement in the breast cancer survival and progression in vivo. A complete evaluation will be also carried out on these human GH/prolactin mice. At the end of the study, we will have a humanized mouse model that recapitulates the hormonal profile of breast cancer patients in terms of prolactin and GH. This mouse model has the potential to be an excellent platform for drug response testing of human breast tumor xenotransplants and for modeling primary cancer tissues from patients for personalized medicine.

    Lay Abstract:
    Breast cancer is the most common cancer in women in the U.S. In recent years, breast cancer research in the laboratory has identified many promising treatment targets due to greater understanding of the molecular mechanisms involved in breast cancer initiation and progression. To translate these findings from laboratory research to clinical care, the therapeutic drug candidates have to show positive results in preclinical evaluations in animal models. Such testing is usually carried out on mice, in which established human breast cancer cells or human tumor samples are grown. However, such testing does not often yield results accordant with the human trials, which may be due to the failure of mouse models to adequately represent the human physiological conditions as the host for the human cancer cells or tissues. Endocrine hormones have been implicated in a number of ways in breast tumor growth and progression. Among the major hormones involved, estrogen and progesterone are steroid hormones which work across species, while the two peptide hormones prolactin (PRL) and growth hormone (GH) have structurally diverged between mice and human. Our hypothesis is that hGH and hPRL in circulation are important for modeling human breast cancer in mice. In the proposed study, we are going to characterize the efficacy of mouse GH (mGH) and human GH (hGH) on benign and malignant human breast tissue taken directly from patients in an ex vivo model system. To overcome the inability of mGH and mouse PRL to activate prolactin and growth hormone receptors in human breast cancer, we will generate mice that express hGH instead of mGH and cross this new mouse into a parallel mouse line that we already have established that expresses physiological levels of human PRL instead of mouse PRL. We are going to test this new hGH/hPRL mouse model for modeling human breast cancer. By comparing the growth and response of the human breast cancer xenotranplants in the hGH/hPRL mice with the wildtype mice, we will get valuable information about the GH/PRL involvement in the breast cancer survival and progression. A complete evaluation will be also carried out on these human GH/prolactin mice. At the end of the study, we will have a humanized mouse model that recapitulates the hormonal profile of breast cancer patients in terms of prolactin and GH. This mouse model has the potential to be an excellent platform for drug response testing of human breast tumor xenotransplants and for modeling primary cancer tissues from patients for personalized medicine.