MammaPrint® (MP) is a 70-gene signature that stratifies early-stage breast cancer patients into low- and high-risk of distant relapse. Further stratification of MP risk results identifies four risk subgroups, Ultra-Low (UL), Low, High 1 and High 2, with specific prognostic and predictive outcomes. BluePrint® (BP) is an 80-gene signature that classifies breast tumors as Basal, Luminal, or HER2 molecular subtype. To gain insight into their biological significance, we annotated the MP 70- and BP 80-genes with respect to the ten hallmarks of cancer (HoC). Furthermore, we related gene expression profiles of the extreme ends of the MP Low risk and High risk patients (here called, Ultra-Low (UL) and Ultra-High (UH) or High2 respectively), to the ten HoC per BP subtype by differential gene expression and pathway analysis.

MP and BP gene functions reflected all ten HoCs. Most MP and BP genes were associated with sustaining proliferative signaling, followed by genome instability and mutation categories. Based on the gene expression profiles, UL and UH subgroup pathways were down -or upregulated, respectively, reflecting proliferative and metastatic features such as G2M checkpoint, DNA repair, oxidative phosphorylation, immune invasion, PI3K/AKT/mTOR signaling, and hypoxia pathways. Notably, the UH HER2-type was enriched in several immune signaling pathways, such as IL2/STAT5 signaling and TNFα signaling via NFκB. Our results show that MP and BP gene signatures represent and capture all ten HoCs and highlight underlying biological processes of MP extreme samples, which might guide treatment decisions as the signature captures the full spectrum of early breast cancers.