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    Awarded Grants
    Radiation and TGF Beta as Mediators of Stromal Activation in Breast Carcinogenesis

    Scientific Abstract:
    Background. Ionizing radiation, such as x-rays and ?-rays, is a known mammary gland carcinogen causing double-strand breaks in the cellular DNA leading to accumulation of mutations. However, ionizing radiation also perturbs the mammary microenvironment, which can contribute to cancer progression. We propose that the mechanistic link between ionizing radiation and breast cancer risk is that radiation leads to stromal processes that can promote malignant progression by initiated cells in the adjacent epithelium. We hypothesize that increased TGF?, remodeled extracellular matrix (ECM), and molecular markers in irradiated stroma are indicative of 'activation'. Our experimental studies and those of others have demonstrated that atypical stroma can become an active participant in cancer progression. TGF?, a cytokine that regulates cell proliferation and differentiation, is activated by ionizing radiation. However, its role in breast cancer is paradoxical in that it can both inhibit and promote carcinogenesis. This may be due to differential effects of its signaling when originating in the stroma versus the epithelium during cancer initiation and progression. Hypothesis. First, activation of mammary stroma controls tumorigenesis of human breast epithelial cells, and second, this process specifically involves TGF?. Specific Aims. (1) Determine the extent of tumorigenic potential of non-malignant, pre-malignant, and malignant epithelium grown in the context of a normal and activated stroma. (2) Test whether TGF? signaling in the epithelium versus the stroma in response to ionizing radiation impacts the ability of epithelium to undergo neoplastic transformation. (3) Define how the stromal versus epithelial origin of TGF? alters tumor progression. Study Design. I will use a new “humanized” mammary gland mouse model where human fibroblasts are transplanted into a mouse mammary gland to facilitate the growth of human mammary epithelium. Differential inhibition of TGF? production by RNAi and disruption of signaling using molecular inhibitors in the stroma versus the epithelium will be used to investigate specific cellular roles of TGF? during tumorigenesis. Potential Outcomes and Benefits. This study is designed to further expand our understanding of epithelial-stromal interactions leading to neoplastic transformation, which can lead to new strategies in cancer prevention and treatment.

    Lay Abstract:
    The National Cancer Institute estimates that more than 1,500 people die each day from cancer making it a second-leading cause of death in the US exceeded only by heart disease. Breast cancer is the most frequently diagnosed cancer in US women, and it is estimated that 215,990 new breast cancer cases will be diagnosed in 2004, and 40,110 women will die from this disease. Ionizing radiation, such as x-rays, is a known mammary gland carcinogen. For a long time it has been thought that the formation of breast tumors is due to radiation-induced genetic mutations in epithelium, the cells that make up mammary gland duct system. However, a number of recent studies have demonstrated that external agents can alter the stroma, the tissue surrounding mammary gland epithelium, which in turn, trigger tumor formation of otherwise non-malignant mammary gland cells. Our own studies have demonstrated that exposure of the mouse mammary gland stroma to ionizing radiation leads to formation of breast tumors by pre-malignant cells. Collectively, this new data strongly points toward the central role of stroma in the tumor formation process. I plan to investigate the interactions between stroma and epithelium to evaluate the extent of stromal control over radiation induced tumor formation using a new “humanized” model system. The mouse stroma will be colonized by human fibroblasts first in order to accept transplanted human cells that will grow and form ductal outgrowth. I will study the changes induced by radiation exposure in both the stroma and epithelial cells, such as cell proliferation, death, and expression of molecular markers known to play a role in tumorigenesis. In this study radiation is both a relevant human carcinogen and a probe to better understand how perturbing cell interactions can affect carcinogenesis. It is designed to translate the findings from basic cellular research to an animal model and expand our insight into the interactions between mammary gland stroma and epithelium. Identification of alterations induced by ionizing radiation in the stroma and the epithelial cells may provide new strategies in cancer prevention and treatment.