Abstract 5168: Unraveling the molecular signature that drives breast cancer-induced brain metastasis in a mouse xenograft model
Authors: Keya De Mukhopadhyay, Abhik Bandyopadhyay, Abdel G. Elkahloun, John E. Cornell, Junhua Yang, LuZhe Sun
Journal: Cancer Research (2011)

Abstract Brain metastases are most feared complication in breast cancer (BCa). Nearly 20% of patients with advanced BCa are eventually diagnosed with brain lesions, making breast tumors the main source of metastatic brain disease in women. Presently available treatment regimens are not capable of significantly treating the BCa-induced brain metastases due to their inability to penetrate the blood brain barrier. Rodent model systems have been reported for brain metastasis in BCa but the current models for brain metastasis have limitations. As such, there is a need of an efficient model system that can significantly contribute towards our understanding of different factors from both host and tumor leading to brain metastasis. Previously we isolated and characterized B6TC cells, derived from the stable spontaneous fusion of MDA-MB-231/GFP/Neo and ZR-75-1/GFP/puro in mouse bone marrow microenvironment. The low ER-expressing B6TC has propensity to metastasize to brain in addition to lung and bone, to express CD44 and ALDH, and to form mammospheres indicating its stem cell-like features. In this study using B6TC, we have developed an efficient and novel mouse model for studying BCa-induced brain metastasis. We performed RNA microarray to identify genes whose RNA levels are significantly altered in B6TC cells by greater than 2-fold at the false discovery rate of 0.001, when compared to the parental metastatic MDA-MB-231 or non-aggressive ZR-75-1 cells. Interestingly we identified genes like MMP1, HB-EGF, ST3GAL1, PTGS2, ITGA3, and CXCR4 implicated in metastasis regulation. Then we derived a Luc-GFP transfected B6TC line and enriched it by 4 successive in vivo passages to obtain a highly aggressive B6TC/Luc-GFP cell line with 100% brain metastatic frequency. A second round of RNA microarray was performed with highly brain metastatic B6TC/Luc-GFP and parental B6TC cells to derive a core signature of up- and down-regulated genes to select unique potential brain metastatic genes by comparing two sets of microarray data. Apart from potent brain metastatic genes detected earlier, we identified ZEB2, an EMT activator, a crucial promoter for metastasis, and a modulator of TGF beta signaling pathway, which shows up-regulation over successive in-vivo passages. Further analyses are underway to establish a refined signature of BCa-induced brain metastasis in our novel model system. Our study is significant in that they suggest potential brain metastasis genes for BCa. This will not only provide valuable insight into molecular mechanism of BCa-induced brain metastasis but also lay the foundation to identify novel prognostic and therapeutic markers of brain metastases, leading ultimately to the discovery of novel molecularly targeted drugs to prevent and eradicate BCa metastasis initiation, progression and recurrence. 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 5168. doi:10.1158/1538-7445.AM2011-5168