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Analysis of radiation therapy in a model of triple-negative breast cancer brain metastasis

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Abstract

Most cancer patients with brain metastases are treated with radiation therapy, yet this modality has not yet been meaningfully incorporated into preclinical experimental brain metastasis models. We applied two forms of whole brain radiation therapy (WBRT) to the brain-tropic 231-BR experimental brain metastasis model of triple-negative breast cancer. When compared to sham controls, WBRT as 3 Gy × 10 fractions (3 × 10) reduced the number of micrometastases and large metastases by 87.7 and 54.5 %, respectively (both p < 0.01); whereas a single radiation dose of 15 Gy × 1 (15 × 1) was less effective, reducing metastases by 58.4 % (p < 0.01) and 47.1 % (p = 0.41), respectively. Neuroinflammation in the adjacent brain parenchyma was due solely to a reaction from metastases, and not radiotherapy, while adult neurogenesis in brains was adversely affected following both radiation regimens. The nature of radiation resistance was investigated by ex vivo culture of tumor cells that survived initial WBRT (“Surviving” cultures). The Surviving cultures surprisingly demonstrated increased radiosensitivity ex vivo. In contrast, re-injection of Surviving cultures and re-treatment with a 3 × 10 WBRT regimen significantly reduced the number of large and micrometastases that developed in vivo, suggesting a role for the microenvironment. Micrometastases derived from tumor cells surviving initial 3 × 10 WBRT demonstrated a trend toward radioresistance upon repeat treatment (p = 0.09). The data confirm the potency of a fractionated 3 × 10 WBRT regimen and identify the brain microenvironment as a potential determinant of radiation efficacy. The data also nominate the Surviving cultures as a potential new translational model for radiotherapy.

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Abbreviations

SRS:

Stereotactic radiosurgery

TN:

Triple-negative

WBRT:

Whole brain radiation therapy

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Acknowledgments

This work was supported by the Intramural Research program of the National Cancer Institute and by the Department of Defense Center of Excellence Breast Cancer Research Program Award W81XWH-06-0033. The authors thank Dr. Yong Qian for excellent animal procedures.

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Author notes

  1. Diane Palmieri

    Present address: NHLBI, Bldg 10-CRC, 10 Center Dr., Bethesda, MD, 20892, USA

Authors and Affiliations

  1. Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Building 10, Room B3B69, 10 Center Dr., Bethesda, MD, 20892, USA

    DeeDee Smart, Alejandra Garcia-Glaessner, Tamalee Kramp, Sudhanshu Shukla & Kevin Camphausen

  2. Women’s Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bldg 37, Rm. 1126, Bethesda, MD, 20892, USA

    Diane Palmieri, Brunilde Gril, Tiffany Lyle, Emily Hua & Patricia S. Steeg

  3. Section on Neuroplasticity, NIMH, NIH, 35 Convent Dr., Bethesda, MD, 20892, USA

    Sarah J. Wong-Goodrich & Heather A. Cameron

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Smart, D., Garcia-Glaessner, A., Palmieri, D. et al. Analysis of radiation therapy in a model of triple-negative breast cancer brain metastasis. Clin Exp Metastasis 32, 717–727 (2015). https://doi.org/10.1007/s10585-015-9739-9

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