Irradiation of Juvenile, but not Adult, Mammary Gland Increases Stem Cell Self-Renewal and Estrogen Receptor Negative Tumors

Authors

  • Jonathan Tang,

    1. Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley California, USA
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  • Ignacio Fernandez-Garcia,

    1. Department of Radiation Oncology, New York University School of Medicine, New York, New York, USA
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  • Sangeetha Vijayakumar,

    1. Department of Radiation Oncology, New York University School of Medicine, New York, New York, USA
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  • Haydeliz Martinez-Ruis,

    1. Department of Radiation Oncology, New York University School of Medicine, New York, New York, USA
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  • Irineu Illa-Bochaca,

    1. Department of Radiation Oncology, New York University School of Medicine, New York, New York, USA
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  • David H. Nguyen,

    1. Department of Radiation Oncology, New York University School of Medicine, New York, New York, USA
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  • Jian-Hua Mao,

    1. Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley California, USA
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  • Sylvain V. Costes,

    Corresponding author
    1. Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley California, USA
    • Correspondence: Mary Helen Barcellos-Hoff, Ph.D., Department of Radiation Oncology, New York University, School of Medicine, 566 First Avenue, New York, New York 10016, USA. Telephone: +1–212-263–3021; e-mail: mhbarcellos-hoff@nyumc.org; or Sylvain V. Costes Ph.D., Department of Cancer and DNA damage responses, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, MS977, Berkeley, California 94720, USA. Telephone: +1–510-486–6988; e-mail: svcostes@lbl.gov

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  • Mary Helen Barcellos-Hoff

    Corresponding author
    1. Department of Radiation Oncology, New York University School of Medicine, New York, New York, USA
    • Correspondence: Mary Helen Barcellos-Hoff, Ph.D., Department of Radiation Oncology, New York University, School of Medicine, 566 First Avenue, New York, New York 10016, USA. Telephone: +1–212-263–3021; e-mail: mhbarcellos-hoff@nyumc.org; or Sylvain V. Costes Ph.D., Department of Cancer and DNA damage responses, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, MS977, Berkeley, California 94720, USA. Telephone: +1–510-486–6988; e-mail: svcostes@lbl.gov

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Abstract

Children exposed to ionizing radiation have a substantially greater breast cancer risk than adults; the mechanism for this strong age dependence is not known. Here we show that pubertal murine mammary glands exposed to sparsely or densely ionizing radiation exhibit enrichment of mammary stem cell and Notch pathways, increased mammary repopulating activity indicative of more stem cells, and propensity to develop estrogen receptor (ER) negative tumors thought to arise from stem cells. We developed a mammary lineage agent-based model (ABM) to evaluate cell inactivation, self-renewal, or dedifferentiation via epithelial-mesenchymal transition (EMT) as mechanisms by which radiation could increase stem cells. ABM rejected cell inactivation and predicted increased self-renewal would only affect juveniles while dedifferentiation could act in both juveniles and adults. To further test self-renewal versus dedifferentiation, we used the MCF10A human mammary epithelial cell line, which recapitulates ductal morphogenesis in humanized fat pads, undergoes EMT in response to radiation and transforming growth factor β (TGFβ) and contains rare stem-like cells that are Let-7c negative or express both basal and luminal cytokeratins. ABM simulation of population dynamics of double cytokeratin cells supported increased self-renewal in irradiated MCF10A treated with TGFβ. Radiation-induced Notch concomitant with TGFβ was necessary for increased self-renewal of Let-7c negative MCF10A cells but not for EMT, indicating that these are independent processes. Consistent with these data, irradiating adult mice did not increase mammary repopulating activity or ER-negative tumors. These studies suggest that irradiation during puberty transiently increases stem cell self-renewal, which increases susceptibility to developing ER-negative breast cancer. Stem Cells 2014;32:649–661

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