Targeting DNA replication before it starts: Cdc7 as a therapeutic target in p53 mutant Her2 and triple negative breast cancer

Excerpt

Based on protein expression profiles of core regulatory proteins involved in the G₁-S and G₂-M phase transitions, we have identified three distinct cell cycle phenotypes in a series of 200 breast cancers: a G₀ out-of-cycle state (18% of cases); a G₁ arrested/delayed state (24% cases); and accelerated S-G₂-M phase progression (58% of cases). The accelerated cell cycle progression phenotype had a higher risk of relapse when compared with G₀ and G₁-delayed/arrested phenotypes (HR = 3.90 (95% CI = 1.81 to 8.4), P < 0.001) and was associated with Her2 and triple negative subtypes (P < 0.001). High-grade tumours with the G₁-delayed/arrested phenotype showed an identical low risk of relapse compared with well-differentiated G₀ tumours. In addition to its prognostic significance, the cell cycle phenotype also impacts on individualised therapeutic decisions. Only patients showing the actively cycling, aggressive cell cycle phenotype are likely to benefit from conventional chemotherapeutic S-phase-directed or M-phase-directed agents or from the new generation of targeted cell cycle inhibitors that are now entering clinical trials. …