Abstract 2846: Pigment epithelium-derived factor (PEDF) functions as a brain metastasis suppressor of breast cancer

Abstract

Abstract Brain metastases occur in 10-20% of metastatic breast cancer patients. The one year survival rate is approximately 20%. Brain metastasis is typically diagnosed late in breast cancer progression; however, studies suggest that the incidence of brain metastasis may be increasing under current chemotherapeutic regimens. We have investigated changes in gene expression associated with the acquisition of brain metastatic potential by breast cancer. A DNA microarray analysis comparing human brain metastases and a cohort of unlinked primary breast carcinomas identified Pigment Epithelium-Derived Factor (PEDF) as down-regulated in the brain metastases relative to the primary tumors (mean ∼14X lower by QPCR validation). The data suggest the hypothesis that PEDF may have a negative impact on brain metastatic progression. PEDF, a secreted factor, has been shown to act as a tumor suppressor, has strong anti-angiogenic activity, but supports the proliferation/viability/ differentiation of neural tissue. We hypothesize that the multiple roles of PEDF make it a potent agent which targets not only tumor cells, but also the microenvironment of the brain. In vitro experiments demonstrated that PEDF can promote death of breast cancer cells. Conversely, PEDF promoted neuronal survival, in vitro. In a xenograft model system (231BR, a brain-tropic derivative of human MDA-MB-231 breast cancer cells) PEDF overexpression inhibited formation of large brain metastases (∼2-fold, p=0.001) and reduced proliferation of PEDF-expressing breast cancer cells in mouse brain metastases (11% Ki67-positive, PEDF-positive vs. >56% Ki67-positive, PEDF-negative). In an intracranial implantation model, expression of PEDF by breast cancer cells lead to a rapid reduction in brain metastatic tumor volume. Histological examination suggests that PEDF reduces gliosis and protects neurons concomitant to suppression of metastatic growth. The data suggest the intriguing possibility that PEDF overexpression may concurrently inhibit brain metastasis of breast cancer cells but preserve neuronal function. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2846. doi:10.1158/1538-7445.AM2011-2846