Abstract B091: Analysis of glial activation in a murine model of brain metastatic breast cancer

Abstract

Abstract Brain metastasis represents a particularly challenging complication of breast cancer. It is estimated that in certain populations of cancer patients, approximately 10-15% have symptomatic brain metastases and as many as 30% reveal metastases on autopsy. The brain provides a unique microenvironment for tumor growth. It is a particularly difficult therapeutic target due to the complexity of brain function as well as the reduced access of therapeutic agents through the blood brain barrier (BBB). In fact, many of the newest and most effective treatments for primary breast cancer are ineffective in treating tumor metastases in the brain. It is becoming increasingly clear that prevention and treatment of brain metastatic breast cancer requires development of new, brain-specific treatments which can take into account this unique metastatic milieu and exploit innate mechanisms to fight tumor cell seeding, extravasation, and growth in the brain. In this study, we characterized pattern of glial activation in a murine model of brain metastatic breast cancer. We used a human breast adenocarcinoma cell line, MDA-MB-231BR-GFP, that exhibits selective metastatic tropism toward the brain. Three weeks after intracardiac injection of the cells into Nu/Nu mice, we observed the development of brain metastases. Using immunohistochemistry, we analyzed expression of glia-specific markers in the immediate vicinity of and away from metastatic breast tumors. We discovered that microglia and astrocytes are activated in the areas adjacent to tumor cells. The degree of activation diminishes considerably away from the tumors. The experimental data provide an insight into the pattern of glial activation in the setting of brain metastatic breast cancer. The results of our experiments also necessitate additional studies to improve our understanding about breast tumor metastasis to the brain. We are currently investigating mechanisms whereby glial activation may promote increased metastatic seeding of breast cancer cells. Our research focus has been on pro-inflammatory markers as potential mediators of glial activation on the entry of cancer cells to the brain. In addition, we have been examining possible contribution of glia in the disruption of the BBB and the increase in brain metastasis of breast cancer. These results provide a starting point for evaluating whether glia may directly contribute to breast cancer metastasis to the brain. Citation Format: Yuriy Shapovalov, Stacy A. Amico-Ruvio, Sara C. Spielman, Cassandra E. Lamantia, Edward B. Brown, III, Ania K. Majewska. Analysis of glial activation in a murine model of brain metastatic breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B091.