Research Grants Awarded
Cancer Stem Cells and Breast Cancer Recurrence
Tumor Cell Biology II
Background: A cardinal feature of human breast cancers is the survival and persistence of residual neoplastic cells following the apparently successful treatment of the primary tumor. Ultimately, these residual cells re-emerge from their dormant state and resume growth, leading to cancer recurrence. The ability of residual tumor cells to survive for many years has raised the possibility that these cells may share important properties with cancer stem cells or normal mammary stem cells. Related to this, it has been proposed that normal mammary stem cells may represent a preferred target for transformation. To address these possibilities, we have developed a series of doxycycline-inducible transgenic mouse models that display key features of human breast cancer progression, including recurrence from residual neoplastic disease. Objective/Hypothesis: We hypothesize that the population of residual neoplastic cells that persist in the mammary gland following tumor regression are enriched for cells that share critical features with mammary stem cells and/or cancer stem cells. Specific Aims: The purpose of this proposal is to use functional tests to determine the relationship between residual neoplastic cells, stem cells, and cancer stem cells and to thereby analyze properties of residual neoplastic cells that are relevant to tumor recurrence. Aim I will determine whether cells with tumorigenic potential are enriched in residual neoplastic lesions. Aim II will determine whether cells bearing markers for mammary stem cells are enriched in residual lesions and whether residual neoplastic cells possess functional properties of mammary stem cells. Aim III will determine whether mammary stem cells are preferential targets for oncogene-induced transformation. Study Design: Oncogene-dependent tumors will be generated by transplanting GFP-labeled primary tumor cells from tumors arising in doxycycline-inducible MYC and Neu transgenic mouse models. Following tumor biopsy, tumor regression will be induced by doxycycline withdrawal and oncogene down-regulation. GFP+ cells within the resulting residual lesions will be isolated and analyzed to determine whether GFP+ residual tumor cells are enriched for tumorigenic cells compared to primary tumors, are enriched for cells expressing mammary stem cell surface markers, or possess functional properties of normal mammary stem cells. Finally, we will determine whether mammary stem cells are preferential targets for oncogene-induced transformation by inducing oncogene expression in prospectively sorted mammary stem cells. Potential Outcomes and Benefits of Research: Tumor recurrence is responsible for the vast majority of breast cancer deaths. Understanding the biology of residual neoplastic cells will shed light on the role of these cells in breast cancer progression and should facilitate the development of more appropriate therapies targeted against this critical subpopulation of tumor cells.
As a consequence of its high incidence and favorable prognosis, breast cancer is the most prevalent cancer in the world today with more than 5 million women currently living with a diagnosis of breast cancer. Among these women, tumor dormancy followed by recurrence - local, regional, or distant - represents the most common cause of mortality from this disease. Consistent with this, nearly 40% of women without clinically recognized spread of their disease harbor breast cancer cells at distant sites in their bodies. Indeed, a cardinal feature of human breast cancers is the survival and persistence of a small number of tumor cells (called residual neoplastic disease) in a presumed dormant state following the apparently successful treatment of the initial tumor. Ultimately, these residual tumor cells re-emerge from their dormant state and resume growth, leading to cancer recurrence. While recurrence constitutes a problem of unrivaled clinical importance, little is known about the mechanisms underlying it other than that recurrent tumors, by definition, arise from residual tumor cells that persist following surgery, chemotherapy, and/or radiation therapy. As such, understanding the biology of residual tumor cells is a critical priority in breast cancer research. Achieving this goal, however, has been hampered by the lack of animal models that faithfully recapitulate this common step in the natural history of this disease. Given the clinical importance of residual neoplastic disease, we have created genetically engineered mouse models for breast cancer in which tumors that have been induced to shrink and disappear leave behind a population of residual neoplastic cells. As in humans, these cells ultimately give rise to tumor recurrences that result in the death of their host. Consequently, this model system provides a unique opportunity to investigate the biology of residual neoplastic cells to understand how these cells are able to survive for long periods of time and eventually regrow. In this application we will use this model to test a new hypothesis that postulates that residual tumor cells that survive following tumor therapy are cancer stem cells or share properties with normal mammary stem cells. If it is true, this would have major implications for the manner in which we treat breast cancers, since the properties of these cells "including their sensitivity to anti-cancer agents" are predicted to differ substantially from the majority of cells present in breast cancers. Since it is this small population of cells that is responsible for relapse from this disease, understanding how to identify, track, and kill residual tumor cells is of paramount importance. We believe that our model system will enable us to make important inroads towards this goal and, in doing so, should ultimately facilitate the development of more appropriate therapies targeted against this critical subpopulation of tumor cells.