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    Research Grants Awarded

    Characterisation of the mammary epithelial cell hierarchy and implications for breast cancer

    Study Section:
    Tumor Cell Biology I

    Scientific Abstract:
    Background: The recent prospective isolation of mammary stem cells (MaSCs) provides an important base for studies on normal development and breast carcinogenesis. Critical questions in the field include the nature of the hierarchy of epithelial cells in mammary tissue and the identification of the counterpart normal breast stem cell. The concept that tumors arise from cancer stem cells which are resistant to many therapies has created immense interest. In support of a potential role for MaSCs in breast cancer, it was recently reported that MaSCs are increased in premalignant mammary tissue from MMTV-wnt-1 mice but tumors have not yet been addressed. To understand cell-types that give rise to human breast cancer, it is necessary to identify the normal cell hierarchy and study how these are affected during tumorigenesis. Objective/Hypothesis: We speculate that different breast tumors reflect the transformation of distinct stem or progenitor subpopulations and that delineation of the epithelial hierarchy within mouse and human mammary tissue is fundamental to understanding breast oncogenesis. Specific Aims: 1. Establish the hierarchy of epithelial cells within the mammary gland. 2. Evaluate the existence of cancer stem cells in mammary tumor-prone mice. 3. Identify the counterpart breast stem cell and breast cancer stem cells in human tissue. 4. Identify whether the stem cell population is aberrant in breast tissue from BRCA1 carriers. Study Design: (1) MaSC-enriched and luminal cell subpopulations will be subdivided further by FACS analysis using an extensive range of antibodies, and tested for stem cell activity by transplantation into fatpads and progenitor activity using established in vitro cellular assays. The expression of the estrogen and progesterone receptors will be determined by immunohistochemistry and the effects of E, P and prolactin on cell proliferation and differentiation assessed in vitro. (2) Expansion of stem/progenitor populations will be examined in premalignant tissue and frank tumors in mulitple tumor-prone strains. Identified subpopulations (using markers from Aim 1) will be transplanted to reveal the tumorigenic fraction. (3) Breast tissue derived from reduction mammoplasties and breast cancer surgery will be fractionated by FACS analysis to identify distinct subpopulations. These will be transplanted at limiting dilution into ?humanised? fat pads of NOD-SCID mice to identify stem cells and tumor-initiating cells, analogous to the approach used above. (4) The studies will be extended to breast tissue derived BRCA1 (and BRCA2) carriers, as in (3). Potential Outcomes and Significance: A prerequisite to understanding the origin of breast cancers is the identification of normal stem cells and the cellular hierarchy in breast. The identification and characterisation of new markers expressed by stem/progenitor cells is of major relevance to the development of novel therapeutic strategies for breast cancer

    Lay Abstract:
    The rare adult stem cell from which all breast epithelial tissue is formed has recently been discovered. Remarkably, a single stem cell was found to be capable of giving rise to various cell types in the breast, including the secretory units that produce milk and the ductal cells that transmit milk to the nipple. These cell types are responsible for the majority of human breast tumors. However, the precise 'cell of origin' from which cancers ultimately develop is not known. The recent discovery that the stem cell population is expanded in at least one model of breast cancer, suggests that some tumors may arise from the breast stem cell itself. Using mouse models and cellular assays, our aim is to characterize the hierarchy of stem, progenitor ('daughter cells') and mature cells in the breast. We will extend these studies to human breast tissue obtained from reduction mammoplasties to identify human breast stem and progenitor cells. These studies will provide insight into the various cell types that give rise to different types of breast cancer. An important evolving concept in cancer biology is that a rare population of cells resident within a tumor, termed 'cancer stem cells', have indefinite growth potential and drive tumor growth. These cells could even account for resistance to conventional anti-cancer treatment, as cells with stem cell-like properties would be able to proliferate extensively and form new tumors. We will apply our knowledge of normal mammary stem cells to determine whether cancer stem cells are present in mouse and human tumors. Ultimately, we wish to identify specific cell surface proteins on stem and precursor cells that could provide therapeutic targets. An ?basal? subtype of breast cancer is the most clinically agressive tumor subtype and may arise from breast stem cells. These tumors are ?triple negative? for the key markers ER, PR and Her2 and are therefore resistant to endocrine therapy (such as Tamoxifen and aromatase inhibitors) and Herceptin. Importantly, tumors arising in BRCA1 carriers are often basal and this has led to speculation that these tumors are originally derived from a stem cell. We hypothesize that the pool of breast stem cells is altered in BRCA1 carriers and that this population of cells becomes progressively expanded. To address this, we will compare our findings on normal human breast tissue and ?sporadic? tumors to breast tissue and tumors collected from BRCA1, BRCA2, ?nonBRCA1/2? women who are members of XXXX, a breast cancer research consortium comprising over 1000 multigenerational multicase families. Our studies will provide new insights into the cell types from which breast cancers arise in sporadic and hereditary breast cancer, and how tumor-forming capacity is modified by cell-type and gene expression. Delineation of cancer-prone cells and cancer stem cells could reveal new markers and provide new therapeutic strategies to target breast cancer.