Abstract
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. The DNA replication initiation factor Cdc7 is an emerging anticancer target. Cdc7 inhibition results in an abortive S phase and potent cancer cell killing. Specificity is based on normal cells undergoing a reversible G1 arrest following Cdc7 inhibition due to activation of a novel cell cycle checkpoint that is lost or impaired in cancer cells. Our analysis of the molecular circuitry underlying this replication origin activation checkpoint reveals that G1 arrest is dependent on three nonredundant checkpoint axes coordinated through the Forkhead transcription factor FoxO3a and p53. We show that only breast cancers displaying the accelerated cell cycle phenotype express elevated Cdc7 levels and are therefore highly represented in p53 mutant Her2-subtype and triple negative tumours. Breast cancers of the luminal subtype expressing low levels of Cdc7 undergo a cytostatic G1 arrest after Cdc7 inhibition due to their p53 wild-type status, a checkpoint response mimicking untransformed cells. In contrast, Her2 and triple negative tumours show a marked response to Cdc7 inhibitors with potent cancer-cell-specific killing as a result of overexpression of the target protein and a result of impairment of the origin activation checkpoint due to p53 lesions. We have thus defined a new therapy and a means of assessing response.
Highlights
The response rarely sustains long among the responders for Herceptin monotherapy treatment
We have provided a novel mechanism of acquired resistance to Herceptin in human epidermal growth factor receptor 2 (HER2)-positive breast cancer and have resolved the inconsistencies in the literature regarding the effect of Herceptin on HER2 phosphorylation
Using a range of biochemical and cell-biology techniques, we have shown that BRCA1 is modified by SUMO in response to genotoxic stress, and co-localises at sites of DNA damage with SUMO1, SUMO2/3 and the SUMO conjugating enzyme Ubc9
Summary
The response rarely sustains long among the responders for Herceptin (trastuzumab) monotherapy treatment. BRCA1 is strongly implicated in the maintenance of genomic stability by its involvement in multiple cellular pathways including DNA damage signalling, DNA repair, cell cycle regulation, protein ubiquitination, chromatin remodelling, transcriptional regulation and apoptosis Both pathological and gene expression profiling studies provide evidence that breast cancers with germline mutations in BRCA1 are different from non-BRCA1-related breast cancers. The vitreous humour is one of the few tissues in the body that is avascular and virtually acellular, and previous studies have indicated that opticin contributes to the maintenance of this state by inhibition of angiogenesis The aim of this present study is to investigate the effect and mode of action of opticin in suppressing tumour cell proliferation and migration in vitro in a panel of breast cancer cell lines and to establish its therapeutic efficacy in human breast tumour xenografts in vivo. Using receptorselective ligands (patent filed by MRC Technology) specific for the TRAIL death receptors, TRAIL-R1/TRAIL-R2, we have previously shown that primary leukaemic cells isolated from patients with chronic lymphocytic leukaemia can be selectively sensitized to apoptosis by combining an a histone deacetylase inhibitor (HDACi) with a TRAIL-R1-specific form of TRAIL/TRAIL-R1 mAb
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