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

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 primar...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2012, Vol.72 (1), p.144-153
Main Authors: FITZGERALD, Daniel P, SUBRAMANIAN, Preeti, HERMAN, Mary M, CAMPHAUSEN, Kevin, PALMIERI, Diane, PATRICIA BECERRA, S, STEEG, Patricia S, DESHPANDE, Monika, GRAVES, Christian, GORDON, Ira, YONGZHEN QIAN, SNITKOVSKY, Yeva, LIEWEHR, David J, STEINBERG, Seth M, PALTAN-ORTIZ, José D
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Apoptosis - physiology
Biological and medical sciences
Breast Neoplasms - pathology
Cell Line, Tumor
Cell Proliferation
Eye Proteins - physiology
Female
Fluorescent Antibody Technique
Gynecology. Andrology. Obstetrics
Humans
Mammary gland diseases
Medical sciences
Mice
Neoplasm Metastasis
Nerve Growth Factors - physiology
Neurology
Neurons - pathology
Pharmacology. Drug treatments
Serpins - physiology
Tumors
Tumors of the nervous system. Phacomatoses
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Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-11-1904