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WNT/beta-catenin mediates radiation resistance of mouse mammary progenitor cells. Proc Natl Acad Sci USA

Department of Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 02/2007; 104(2):618-23. DOI: 10.1073/pnas.0606599104
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ABSTRACT Recent studies have identified a subpopulation of highly tumorigenic cells with stem/progenitor cell properties from human breast cancers, and it has been suggested that stem/progenitor cells, which remain after breast cancer therapy, may give rise to recurrent disease. We hypothesized that progenitor cells are resistant to radiation, a component of conventional breast cancer therapy, and that that resistance is mediated at least in part by Wnt signaling, which has been implicated in stem cell survival. To test this hypothesis, we investigated radioresistance by treating primary BALB/c mouse mammary epithelial cells with clinically relevant doses of radiation and found enrichment in normal progenitor cells (stem cell antigen 1-positive and side population progenitors). Radiation selectively enriched for progenitors in mammary epithelial cells isolated from transgenic mice with activated Wnt/beta-catenin signaling but not for background-matched controls, and irradiated stem cell antigen 1-positive cells had a selective increase in active beta-catenin and survivin expression compared with stem cell antigen 1-negative cells. In clonogenic assays, colony formation in the stem cell antigen 1-positive progenitors was unaffected by clinically relevant doses of radiation. Radiation also induced enrichment of side population progenitors in the human breast cancer cell line MCF-7. These data demonstrate that, compared with differentiated cells, progenitor cells have different cell survival properties that may facilitate the development of targeted antiprogenitor cell therapies.

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Available from: Wendy Ann Woodward, Aug 30, 2015
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    • "In addition , the DDR in MaSCs has been difficult to study in vivo mainly because of their low frequency. In culture systems, it has been shown that MaSCs and mammary progenitor cells are more resistant to DNA damage due to upregulation of p21 and WNT signaling, respectively (Insinga et al., 2013; Woodward et al., 2007). However, it is still largely unknown how MaSCs react to DNA damage in vivo within the intact microenvironment and their appropriate niche. "
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    • "These are called cancer stem cells (CSC). Classically, CSC are defined by three major in vitro properties: formation of spherical colonies in culture suspension, differential levels and patterns of surface markers, and increased survival after radiation or chemotherapeutic treatment [3] [4] [5] [6] [7]. Moreover, in experimental models, those CSC are the only tumor cells able to initiate the development of new tumors in heterotopic or homotopic xenotransplantation experiments. "
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    • "Several factors have been found to be correlated with the resistance of CSCs to chemotherapy and radiotherapy. According to a study, the Wnt signaling pathway is implicated in stem cell survival [8]. In glioblastoma, it has been demonstrated that the CD133 cells display strong capability on tumor's resistance to chemotherapy and this resistance is probably due to high expression of BCRP1 and MGMT, as well as anti-apoptosis protein and inhibitors [9]. "
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