BACKGROUND: Breast tumors have been described by molecular subtypes 
characterized by pervasively different gene expression profiles. The subtypes 
are associated with different clinical parameters and origin of precursor cells. 
However, the biological pathways and chromosomal aberrations that differ between 
the subgroups are less well characterized. The molecular subtypes are associated 
with different risk of metastatic recurrence of the disease. Nevertheless, the 
performance of these overall patterns to predict outcome is far from optimal, 
suggesting that biological mechanisms that extend beyond the subgroups impact 
metastasis.
RESULTS: We have scrutinized publicly available gene expression datasets and 
identified molecular subtypes in 1,394 breast tumors with outcome data. By 
analysis of chromosomal regions and pathways using "Gene set enrichment 
analysis" followed by a meta-analysis, we identified comprehensive mechanistic 
differences between the subgroups. Furthermore, the same approach was used to 
investigate mechanisms related to metastasis within the subgroups. A striking 
finding is that the molecular subtypes account for the majority of biological 
mechanisms associated with metastasis. However, some mechanisms, aside from the 
subtypes, were identified in a training set of 1,239 tumors and confirmed by 
survival analysis in two independent validation datasets from the same type of 
platform and consisting of very comparable node-negative patients that did not 
receive adjuvant medical therapy. The results show that high expression of 5q14 
genes and low levels of TNFR2 pathway genes were associated with poor survival 
in basal-like cancers. Furthermore, low expression of 5q33 genes and 
interleukin-12 pathway genes were associated with poor outcome exclusively in 
ERBB2-like tumors.
CONCLUSION: The identified regions, genes, and pathways may be potential drug 
targets in future individualized treatment strategies.