Abstract 1438: Influence of the neural environment on the gene expression profile of metastatic breast cancer

Introduction: Breast cancer is the second most common solid malignancy to metastasize to the central nervous system (CNS), causing severe morbidity and mortality. Understanding the influence of the neural environment on metastatic breast cancer may allow us to begin to more appropriately define therapeutic targets specific to CNS metastases of breast cancer. We therefore sought to determine the effects of the neural environment on the gene expression profiles of multiple breast cancer cell lines. Methods: Three breast cancer cell lines, MCF-7, MDAMB-231 and MDAMB-157, were grown both in vitro as adherent monolayers and as intracranial xenografts in mice. Gene expression profiles were determined using cDNA microarrays. Differentially expressed genes were determined by the Statistical Analysis of Microarrays (SAM) application. Differentially expressed genes were organized into Gene Ontology (GO) pathways using the program GOstat, and further analyzed using the Ingenuity Pathway Analysis (IPA) software to determine relevant cellular pathways. Results: Using SAM analysis of the gene expression profiles, we identified 146 unique genes that were commonly overexpressed and 149 unique genes that were commonly underexpressed across all three cell lines in the intracranial environment compared to the in vitro environment. A subset of the gene cohort overexpressed in the intracranial group distributed into GO pathways related to developmental processes, such as nervous system development (18 genes, p=7*10 −8 ) and brain development (5 genes, p=0.007). Conversely, a large subset of the gene cohort underexpressed in the intracranial group distributed into significant biological GO pathways related to cell cycle and cell death, such as regulation of mitosis (6 genes, p=2*10 −6 ) and apoptosis (12 genes, p=0.005), respectively. The three most statistically significant molecular networks using Ingenuity Pathway Analysis of the common differentially expressed genes were (a) Lipid Metabolism, Molecular Transport, Small Molecule Biochemistry (15 focus molecules, score of 21), (b) Cancer, Gene Expression, Developmental Disorder (15 focus molecules, score of 21), and (c) Cell Cycle, Tumor Morphology, Cellular Growth and Proliferation (12 focus molecules, score of 15). Merging these top three networks yielded important overexpressed hub molecules that are potentially important to breast cancer brain metastases cancer biology, including estrogen receptor 1 (ESR1), erbB3, MAP2K4, TNFSF10 and MMP7. Conclusion: There are statistically significant differences in the gene expression profiles of breast cancer cells grown as intracranial tumors compared to in vitro culture. The differentially expressed genes suggest potential therapeutic targets for breast cancer metastatic to the CNS, such as erbB3, an important signal transduction protein involved in cellular transformation, proliferation and migration. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1438.