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    Awarded Grants
    Characterizing the Beta-Catenin Transgenic Model of Hormone-Independent Breast Cancer

    Scientific Abstract:
    Characterizing The Beta-Catenin Transgenic Model Of Hormone-Independent Breast Cancer. Suppression of beta-catenin signaling prevents alveolar development during pregnancy. Transgenic expression of activated beta-catenin induces precocious alveologenesis and adenocarcinomas. Together these data suggest links between a normal physiological role of beta-catenin during alveolar development and breast cancer. Epidemiological studies of survivors of the atomic bomb have shown that breast cancers arise many years after exposure to irradiation. This latency suggests that breast cancer results from mutations within long-lived progenitor cells. This model is also supported by findings that only a small percentage of cells derived from human breast tumors can perpetuate tumors when injected into mouse mammary fatpads. Beta-catenin tumors are enriched in putative mammary progenitors. These progenitors are further increased by the absence of cyclin D1, a target gene that is essential for alveolar differentiation and retards beta-catenin induced mammary tumor development. Our preliminary data show that beta-catenin-induced mammary tumors lack both estrogen and progesterone receptors and therefore represent hormone-independent mammary tumors. Our objective is to characterize stages in the development of these hormone-independent tumors and to isolate and examine the relationship of alveolar progenitor cells to their later cancer stem cell cousins. We propose to determine critical stages in the progression towards hormone-independent status by examining hormone receptor expression in samples from the earliest hyperplasias to the later adenocarcinomas in MMTV-beta-catenin mice. We will identify cells that respond to beta-catenin signaling by crossing mice expressing a fluorescent reporter of this event to the MMTV-beta-catenin mice. These cells will be isolated and their gene expression profiles characterized. We will examine their survival response to irradiation and chemotherapy. Human hormone receptor-negative tumors will be examined for activation of beta-catenin signaling pathways. Characterization of these cell populations will provide genetic profiles permitting detection of their human counterparts, which we believe are responsible for the high rates of tumor recurrence. They will also provide valuable in vivo and in vitro models that will permit assessment of the efficacy of therapeutic strategies designed to eradicate the stem cell source of breast tumors.

    Lay Abstract:
    Characterizing A Mouse Model Of Hormone-Independent Breast Cancer. Studies of survivors of the atomic bomb have shown that breast cancers form many years after exposure to radiation. This long delay suggests that breast cancers must form from damage (mutations) to long-lived parental cells known as stem or progenitor cells, rather than to their daughter cells. This “stem cell” model of breast cancer is supported by fact that only a small percentage of cells within human tumors can produce new tumors when injected into mice. Current therapies measure success by their ability to reduce tumor bulk, which is formed by the harmless daughter cells that cannot form new tumors. They fail because they have not killed the parental cell source of the tumor. We have shown that mice making increased amounts of a protein, beta-catenin, show inappropriate early breast development and go on to form breast tumors. These studies suggest a link between normal breast development and breast cancer. The breasts of these mice have an excess of parental cells and their tumors lack both estrogen and progesterone receptors. Although 70% of human breast cancers are estrogen receptor positive, estrogen-receptor negative breast cancer is associated with poor response to tamoxifen and poor patient survival. Our mice may therefore provide an important model system to study this type of breast cancer. Our goal is to characterize how hormone-independent tumors progress and the response of parental cells to therapy. We aim to isolate parental progenitor cells from normal mouse breast and to compare them to their cancer stem cell cousins found within the beta-catenin-induced tumors. We will determine critical stages in the development of these breast tumors by examining at when hormone receptors are lost. We will breed our mice to others that are designed to make a green jelly-fish protein only when they encounter beta-catenin. This protein glows under an ultraviolet light allowing us to see the cancer-producing parental cells and distinguish them form their daughters. In this way we can test if these parental cells survive radiotherapy and chemotherapy. We will purify these cells and examine which specific proteins they produce. This “fingerprint” will be used to examine human breast tumors for the presence of parental progenitor cells, which we believe are responsible for tumor recurrence. Our mice will also provide valuable animal and cell models that will permit assessment of novel therapies designed to eradicate the parental cell source of breast tumors.