Abstract 3390: Delineating the molecular signature of the breast cancer-induced brain metastasis and the role of a novel pan-TGF-β inhibitor to block brain metastasis in a mouse xenograft model

Abstract

Breast cancer (BCa) is the most common malignant disease in women in U.S. Nearly 20% of patients with advanced BCa is eventually diagnosed with brain lesions. The available treatment regimens are not capable of significantly treating the BCa-induced brain metastases due to their inability to penetrate the blood brain barrier. The exact molecular mechanism for metastases of BCa into brain is unknown. The current rodent model systems for BCa brain metastasis have limitations. Therefore, there is a need of efficient model system that can significantly contribute towards our understanding of different factors from both host and tumor leading to brain metastasis. Previously we reported estrogen-independent B6TC cell, derived from the stable spontaneous fusion of MDA-MB-231 and ZR-75-1 cells in mouse bone-marrow microenvironment, which has propensity to metastasize to brain when inoculated through intracardiac route, and express stem cell-like features. In this study using B6TC, we have developed an efficient and novel mouse model for studying BCa-induced brain metastasis and investigated the role of a potent pan-TGF-β inhibitor, BGERII, for blocking brain metastasis. We have generated three cell lines from B6TC through three successive rounds of inoculation in mouse and isolation of brain metastatic cells. Each round of selection enhanced the brain metastatic propensity. An initial microarray analysis identified genes implicated in metastasis regulation- MMP1, HB-EGF, ST3GAL1, PTGS2, ITGA3, and CXCR4, showing significant up-regulation in B6TC compared to its parental MDA-MB-231 and ZR-75-1 cells. Analyses of second round of RNA microarray, performed with three sub-lines of B6TC with successively enhanced brain metastatic propensity over generations, identified some molecular pathways, including TGF beta signaling pathway that are associated with enhanced brain metastasis. We next investigated whether metastatic tumor growth in the brain microenvironment can be inhibited by systemic administration of a potent pan-TGF-β inhibitor, BGERII- a recombinant fusion protein containing the endoglin domain of betaglycan (BGE) and the extracellular domain of RII. The animals were inoculated intracardically with N3LR, the most potent sub-line of highly metastatic B6TC cells and were then treated with vehicle or BGERII systemically via i.p. injection right after the inoculation. After three weeks, the BGERII treated group showed lower brain metastasis incidence and tumor burden as detected by whole mouse bioluminescence and GFP imaging. Further analyses to understand the underlying molecular and regulatory mechanism of brain metastasis and its intervention in our mouse model is underway for 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 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3390. doi:1538-7445.AM2012-3390

Integrating Structure to Protein-Protein Interaction Networks That Drive Metastasis to Brain and Lung in Breast Cancer

“…We used HPRD [ 34 ], UNIPROT [ 40 , 41 ] and TIGER[ 42 ] databases for checking the expression of genes in breast tissue.…”

“…We obtained the available point mutations related with cancer from COSMIC [ 54 ] database and humsavar.txt of UNIPROT database. UNIPROT [ 40 , 41 ] provides the variants of a protein’s amino-acid sequence. These variations can be polymorphisms, variations between strains, isolates or cultivars, disease-associated mutations or RNA editing events.…”