Woodward WA, Chen MS, Behbod F, Alfaro MP, Buchholz TA, Rosen JMWNT/beta-catenin mediates radiation resistance of mouse mammary progenitor cells. Proc Natl Acad Sci USA 104(2): 618-623

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: 9.67). 02/2007; 104(2):618-23. DOI: 10.1073/pnas.0606599104
Source: PubMed


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.

Download full-text


Available from: Wendy Ann Woodward
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Adult stem cells and tumor-initiating cells (TICs) often employ different mechanisms of DNA damage response (DDR) as compared to other tissue cell types. However, little is known about how mammary stem cells (MaSCs) and mammary TICs respond to DNA damage. Using the mouse mammary gland and syngeneic p53-null tumors as models, we investigated the molecular and physiological consequences of DNA damage in wild-type MaSCs, p53-null MaSCs, and p53-null TICs. We showed that wild-type MaSCs and basal cells are more resistant to apoptosis and exhibit increased non-homologous end joining (NHEJ) activity. Loss of p53 in mammary epithelium affected both cell-cycle regulation and DNA repair efficiency. In p53-null tumors, we showed that TICs are more resistant to ionizing radiation (IR) due to decreased apoptosis, elevated NHEJ activity, and more-rapid DNA repair. These results have important implications for understanding DDR mechanisms involved in both tumorigenesis and therapy resistance. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Aug 2015 · Stem Cell Reports
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Metastases are the hallmark of cancer. This event is in direct relationship with the ability of cancer cells to leave the tumor mass and travel long distances within the bloodstream and/or lymphatic vessels. Glioblastoma multiforme (GBM), the most frequent primary brain neoplasm, is mainly characterized by a dismal prognosis. The usual fatal issue for GBM patients is a consequence of local recurrence that is observed most of the time without any distant metastases. However, it has recently been documented that GBM cells could be isolated from the bloodstream in several studies. This observation raises the question of the possible involvement of glioblastoma-circulating cells in GBM deadly recurrence by a " homing metastasis " process. Therefore, we think it is important to review the already known molecular mechanisms underlying circulating tumor cells (CTC) specific properties, emphasizing their epithelial to mesenchymal transition (EMT) abilities and their possible involvement in tumor initiation. The idea is here to review these mechanisms and speculate on how relevant they could be applied in the forthcoming battles against GBM.
    Full-text · Article · Apr 2015 · Stem cell International
  • Source
    • "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]. "

    Full-text · Article · Jan 2015 · Journal of Cancer Therapy
Show more