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Modeling Breast Cancer Initiation Through Genetic Manipulation of Mammary Stem Cells
Tumor Cell Biology V
Tumor stem cell theory implies that cancer initiates in a self-renewing multi-potent progenitor. Gene expression profiling of human breast cancers has identified five distinct breast cancer subtypes, suggesting that distinct subtypes of human breast cancer may arise from common precursors. During reproductive life, the lactogenic portion of the mammary gland undergoes periodic and successive regenerative cycles. Initiation of each cycle relies upon a population of self-renewing basal progenitors (SRBPs) possessing retained proliferative capacity, developmental potency and the ability to resist terminal differentiation. These features enable SRBPs to accumulate mutations, harbor them from the protective effects of apoptosis and propagate them into discreet mammary epithelial lineages during subsequent cycles. This implicates mammary SRBPs as the site of breast cancer initiation and is consistent with the high degree of cellular heterogeneity observed in human breast cancers. It further suggests that oncogenic transformation of multi-potent mammary SRBPs may be sufficient to account for the five subtypes of human breast cancer. While this tumor stem cell theory of breast carcinogenesis has many attractive elements, several important questions remain. Tumorigenic stem cells have been isolated from human breast cancers, however it is currently unclear if they are the result of activation of oncogenic pathways within mammary SRBPs. Here we propose to address this question by engineering a transgenic expression system to specifically target oncogenic alleles into mammary SRBPs. The proposed system employs epithelial progenitor-specific promoters fused to a loxP-flanked PGK-neo and the proto-oncogene c-myc. Mammary-specific Cre-mediated excision will result in overexpression of c-myc in mammary SRBPs. This model will extend current studies, in which ectopic expression of c-myc in a basal progenitor cell culture model was sufficient for transformation. These studies indicate that ectopic c-myc activates the canonical Wnt signaling pathway, which is oncogenic and disrupts the non-canonical Wnt pathway, via silencing of the tumor suppressor e-cadherin. Establishment of a transgenic model that enables direct targeting of mammary progenitors will enable a test of our hypothesis which holds that the nature of the oncogenic lesion in mammary SRBPs is a critical determinant of the resulting breast cancer subtype.
There is near universal agreement that all cancers including breast cancer arise from a single cell that has acquired growth and survival advantages over its normal counterparts. It is equally clear that the initiation and progression of breast cancer requires several genetic events or mutations to achieve these advantages. These two facts coupled to studies that indicate that initiation and progression of breast cancer occurs over a period of several years suggest that the earliest mutations must occur in and be harbored by cells with a very long lifespan. The vast majority of cells within the portion of the mammary gland from which all breast cancers arise have a remarkably short lifespan that begins and ends within a single regenerative cycle. In non-pregnant females the regenerative cycle is synchronized with the menstrual cycle. It begins with an impressive wave of cellular proliferation that populates the gland with new cells and, in the absence of a pregnancy, ends with an equally impressive wave of cell death. In pregnant females the cycle begins with a more pronounced wave of proliferation resulting in cells that acquire the ability to produce milk in a process referred to as terminal differentiation. These cells are also fated to die at the end of milk production. In order for this cycle to repeat itself over the course of reproductive life, a highly specialized subset of cells, known as mammary progenitors, must exist that retain their ability to proliferate and resist terminal differentiation. These features confer upon these progenitors a prolonged lifespan, suggesting that they live long enough to accumulate and harbor the mutations necessary for breast cancer initiation. This suggests that breast cancer initiation occurs solely within mammary progenitor cells, which is a hallmark of the stem cell theory of breast carcinogenesis. Here we propose a series of studies aimed at genetic proof of the theory. We propose to generate an animal model in which cancer-causing genes are activated exclusively in mammary progenitor cells. The ability to do this will enable studies that will test several of the basic tenets of the stem cell theory and will enable future studies in which we hope to determine if the clinical diversity of breast cancer results from the nature of the cancer causing gene that initiated it. Experimental proof of this theory will have a profound impact on our ability to prevent and treat breast cancer.