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Opposing Effects of Pigment Epithelium-Derived Factor on Breast Cancer Cell versus Neuronal Survival: Implication for Brain Metastasis and Metastasis-Induced Brain Damage

  1. Author:
    Fitzgerald, D. P.
    Subramanian, P.
    Deshpande, M.
    Graves, C.
    Gordon, I.
    Qian, Y. Z.
    Snitkovsky, Y.
    Liewehr, D. J.
    Steinberg, S. M.
    Paltan-Ortiz, J. D.
    Herman, M. M.
    Camphausen, K.
    Palmieri, D.
    Becerra, S. P.
    Steeg, P. S.

  2. Author Address

    [Steeg, Patricia S.] NCI, Womens Canc Sect, Mol Pharmacol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Subramanian, Preeti; Deshpande, Monika; Becerra, S. Patricia] NEI, Sect Prot Struct & Funct, Lab Retinal Cell & Mol Biol, Bethesda, MD 20892 USA. [Graves, Christian; Gordon, Ira; Camphausen, Kevin] NCI, Radiat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Liewehr, David J.; Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, Bethesda, MD 20892 USA. [Snitkovsky, Yeva; Paltan-Ortiz, Jose D.; Herman, Mary M.] NIMH, Sect Neuropathol, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. [Qian, Yongzhen] NCI, Lab Anim Sci Program, Applicat Int Corp, Frederick, MD 21701 USA.;Steeg, PS (reprint author), NCI, Womens Canc Sect, Mol Pharmacol Lab, Ctr Canc Res,NIH, Bldg 37,Room 1122, Bethesda, MD 20892 USA;steegp@mail.nih.gov
    1. Year: 2012
    2. Date: Jan
  2. Journal: Cancer Research
    1. 72
    2. 1
    3. Pages: 144-153
  4. Type of Article: Article
  5. ISSN: 0008-5472
  1. Abstract:

    Brain metastases are a significant cause of morbidity and mortality for patients with cancer, yet preventative and therapeutic options remain an unmet need. The cytokine pigment epithelium-derived factor ( PEDF) is downregulated in resected human brain metastases of breast cancer compared with primary breast tumors, suggesting that restoring its expression might limit metastatic spread. Here, we show that outgrowth of large experimental brain metastases from human 231-BR or murine 4T1-BR breast cancer cells was suppressed by PEDF expression, as supported by in vitro analyses as well as direct intracranial implantation. Notably, the suppressive effects of PEDF were not only rapid but independent of the effects of this factor on angiogenesis. Paralleling its cytotoxic effects on breast cancer cells, PEDF also exerted a prosurvival effect on neurons that shielded the brain from tumor-induced damage, as indicated by a relative 3.5-fold reduction in the number of dying neurons adjacent to tumors expressing PEDF. Our findings establish PEDF as both a metastatic suppressor and a neuroprotectant in the brain, highlighting its role as a double agent in limiting brain metastasis and its local consequences. Cancer Res; 72( 1); 144-53. (C) 2012 AACR.

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External Sources

  1. View Full Text
  2. DOI: 10.1158/0008-5472.can-11-1904
  3. View record in Web of Science®
  4. WOS: 000298755600015

Library Notes

  1. Fiscal Year: FY2011-2012
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