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Background  Breast cancer brain metastases (BCBM) develop in about 20–30% of breast cancer (BC) patients. BCBM are associated with dismal prognosis not at least due to lack of valuable molecular therapeutic targets. The aim of the study was to identify new molecular biomarkers and targets in BCBM by using complementary state-of-the-art techniques.    Methods  We compared array expression profiles of three BCBM with 16 non-brain metastatic BC and 16 primary brain tumors (prBT) using a false discovery rate (FDR)  p  < 0.05 and fold change (FC) > 2. Biofunctional analysis was conducted on the differentially expressed probe sets. High-density arrays were employed to detect copy number variations (CNVs) and whole exome sequencing (WES) with paired-end reads of 150 bp was utilized to detect gene mutations in the three BCBM.    Results  The top 370 probe sets that were differentially expressed between BCBM and both BC and prBT were in the majority comparably overexpressed in BCBM and included, e.g. the coding genes  BCL3 ,  BNIP3 ,  BNIP3P1 ,  BRIP1 ,  CASP14 ,  CDC25A ,  DMBT1 ,  IDH2 ,  E2F1 ,  MYCN ,  RAD51 ,  RAD54L , and  VDR . A number of small nucleolar RNAs (snoRNAs) were comparably overexpressed in BCBM and included  SNORA1 ,  SNORA2A ,  SNORA9 ,  SNORA10 ,  SNORA22 ,  SNORA24 ,  SNORA30 ,  SNORA37 ,  SNORA38 ,  SNORA52 ,  SNORA71A ,  SNORA71B ,  SNORA71C ,  SNORD13P2 ,  SNORD15A ,  SNORD34 ,  SNORD35A ,  SNORD41 ,  SNORD53 , and  SCARNA22 . The top canonical pathway was entitled, role of BRCA1 in DNA damage response. Network analysis revealed key nodes as Akt, ERK1/2, NFkB, and Ras in a predicted activation stage. Downregulated genes in a data set that was shared between BCBM and prBT comprised, e.g. BC cell line invasion markers JUN, MMP3, TFF1, and HAS2. Important cancer genes affected by CNVs included  TP53 ,  BRCA1 ,  BRCA2 ,  ERBB2 ,  IDH1 , and  IDH2 . WES detected numerous mutations, some of which affecting BC associated genes as  CDH1 ,  HEPACAM , and  LOXHD1 .    Conclusions  Using complementary molecular genetic techniques, this study identified shared and unshared molecular events in three highly aberrant BCBM emphasizing the challenge to detect new molecular biomarkers and targets with translational implications. Among new findings with the capacity to gain clinical relevance is the detection of overexpressed snoRNAs known to regulate some critical cellular functions as ribosome biogenesis.    Electronic supplementary material  The online version of this article (10.1186/s12967-017-1370-x) contains supplementary material, which is available to authorized users.

Comprehensive molecular biomarker identification in breast cancer brain metastases