Abstract
Our objectives were to determine whether clinic-pathological markers and immune-related gene signatures in breast cancer exhibit any change upon brain metastasis and whether previously reported genes significantly associated with brain metastases and the epithelial-mesenchymal transition (EMT) were reproducible and consistent in our dataset. Sixteen pair-matched samples from primary breast cancers and brain metastases diagnosed were collected from the Japan Clinical Oncology Group Breast Cancer Study Group. Gene expression profiles for immune-, brain metastases-, and EMT-related genes were compared between primary breast cancers and brain metastases. Potential therapeutic target genes of 41 FDA-approved or under-investigation agents for brain metastases were explored. Immune-related signatures exhibited significantly lower gene expression in brain metastases than in primary breast cancers. No significant differences were detected for the majority of genes associated with brain metastases and EMT in the two groups. Among 41 therapeutic target candidates, VEGFA and DNMT3A demonstrated significantly higher gene expression in brain metastases. We found that distinct patterns of gene expression exist between primary breast cancers and brain metastases. Further studies are needed to explore whether these distinct expression profiles derive from or underlie disease status and compare these features between metastases to the brain and other sites.
Highlights
Our objectives were to determine whether clinic-pathological markers and immune-related gene signatures in breast cancer exhibit any change upon brain metastasis and whether previously reported genes significantly associated with brain metastases and the epithelial-mesenchymal transition (EMT) were reproducible and consistent in our dataset
Bos et al.[3] reported that gene expression analysis of brain metastatic cells and clinical samples identified the genes for cyclooxygenase (COX2, known as prostaglandin-endoperoxide synthase 2: PTGS2), the epidermal growth factor receptor (EGFR) ligand heparin binding EGF like growth factor (HBEGF), and an a2,6-sialyltransferase (ST6GALNAC5) as mediators of cancer cell passage through the BBB3
The overall percentage of tumor-infiltrating lymphocytes (TILs) out of all live cells was shown to be significantly higher in primary breast cancers than that in metastatic tumor samples, which did not change according to each breast cancer subtype[8]
Summary
Our objectives were to determine whether clinic-pathological markers and immune-related gene signatures in breast cancer exhibit any change upon brain metastasis and whether previously reported genes significantly associated with brain metastases and the epithelial-mesenchymal transition (EMT) were reproducible and consistent in our dataset. Gene expression profiles for immune-, brain metastases-, and EMT-related genes were compared between primary breast cancers and brain metastases. Silva et al.[5] and Vareslija et al.[6] analyzed 39 and 21 matched pairs of primary breast cancers and brain metastases, revealing that the genes for human epidermal growth factor receptor 3 (ERBB3) and RET were significantly overexpressed in brain metastases relative to matched primary tumors. Another key question to brain metastases is the role of immune modulation. We reported fewer TILs in brain metastases than in primary breast cancers by paired matched samples[10]
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