title: Analysis of radiation therapy in a model of triple-negative breast cancer brain metastasis.
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.
authors: Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Building 10, Room B3B69, 10 Center Dr., Bethesda, MD, 20892, USA. smartd@mail.nih.gov.
authors: DeeDee
authors: D
authors: Smart
authors: Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Building 10, Room B3B69, 10 Center Dr., Bethesda, MD, 20892, USA.
authors: Alejandra
authors: A
authors: Garcia-Glaessner
authors: Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bldg 37, Rm. 1126, Bethesda, MD, 20892, USA.|NHLBI, Bldg 10-CRC, 10 Center Dr., Bethesda, MD, 20892, USA.
authors: Diane
authors: D
authors: Palmieri
authors: Section on Neuroplasticity, NIMH, NIH, 35 Convent Dr., Bethesda, MD, 20892, USA.
authors: Sarah J
authors: SJ
authors: Wong-Goodrich
authors: Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Building 10, Room B3B69, 10 Center Dr., Bethesda, MD, 20892, USA.
authors: Tamalee
authors: T
authors: Kramp
authors: Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bldg 37, Rm. 1126, Bethesda, MD, 20892, USA.
authors: Brunilde
authors: B
authors: Gril
authors: Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Building 10, Room B3B69, 10 Center Dr., Bethesda, MD, 20892, USA.
authors: Sudhanshu
authors: S
authors: Shukla
authors: Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bldg 37, Rm. 1126, Bethesda, MD, 20892, USA.
authors: Tiffany
authors: T
authors: Lyle
authors: Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bldg 37, Rm. 1126, Bethesda, MD, 20892, USA.
authors: Emily
authors: E
authors: Hua
authors: Section on Neuroplasticity, NIMH, NIH, 35 Convent Dr., Bethesda, MD, 20892, USA.
authors: Heather A
authors: HA
authors: Cameron
authors: Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Building 10, Room B3B69, 10 Center Dr., Bethesda, MD, 20892, USA.
authors: Kevin
authors: K
authors: Camphausen
authors: Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bldg 37, Rm. 1126, Bethesda, MD, 20892, USA. steegp@mail.nih.gov.
authors: Patricia S
authors: PS
authors: Steeg
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000532:radiotherapy* / Q000556:secondary*; D045744:Cell Line, Tumor; D016371:Cranial Irradiation / Q000379:methods*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011836:Radiation Tolerance; D011879:Radiotherapy Dosage; D064726:Triple Negative Breast Neoplasms / Q000532:radiotherapy* / Q000556:secondary*; D023041:Xenograft Model Antitumor Assays
keywords: Brain; Breast; Cancer; Metastasis; Radiation; Radiosensitivity