ABSTRACT
BACKGROUND: Neoadjuvant chemotherapy is a key component of breast cancer treatment regimens and pathologic complete response to this therapy varies among patients. This is presumably due to differences in the molecular mechanisms that underlie each tumor's disease pathology. Developing genomic clinical assays that accurately categorize responders from non-responders can provide patients with the most effective therapy for their individual disease. METHODS: We applied our previously developed E2F4 genomic signature to predict neoadjuvant chemotherapy response in breast cancer. E2F4 individual regulatory activity scores were calculated for 1129 patient samples across 5 independent breast cancer neoadjuvant chemotherapy datasets. Accuracy of the E2F4 signature in predicting neoadjuvant chemotherapy response was compared to that of the Oncotype DX and MammaPrint predictive signatures. RESULTS: In all datasets, E2F4 activity level was an accurate predictor of neoadjuvant chemotherapy response, with high E2F4 scores predictive of achieving pathologic complete response and low scores predictive of residual disease. These results remained significant even after stratifying patients by estrogen receptor (ER) status, tumor stage, and breast cancer molecular subtypes. Compared to the Oncotype DX and MammaPrint signatures, our E2F4 signature achieved similar performance in predicting neoadjuvant chemotherapy response, though all signatures performed better in ER+ tumors compared to ER- ones. The accuracy of our signature was reproducible across datasets and was maintained when refined from a 199-gene signature down to a clinic-friendly 33-gene panel. CONCLUSION: Overall, we show that our E2F4 signature is accurate in predicting patient response to neoadjuvant chemotherapy. As this signature is more refined and comparable in performance to other clinically available gene expression assays in the prediction of neoadjuvant chemotherapy response, it should be considered when evaluating potential treatment options.
Subject(s)
Breast Neoplasms , E2F4 Transcription Factor/analysis , E2F4 Transcription Factor/metabolism , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Chromatin Immunoprecipitation , Databases, Factual , E2F4 Transcription Factor/chemistry , E2F4 Transcription Factor/genetics , Female , Humans , Neoadjuvant Therapy , Prognosis , ROC CurveABSTRACT
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Subject(s)
Humans , Male , Female , E2F4 Transcription Factor/analysis , E2F4 Transcription Factor , Colorectal Neoplasms/diagnosis , Early Diagnosis , Alleles , DNA/analysis , DNA/isolation & purification , RNA/analysisABSTRACT
Sporadic Burkitt lymphoma (sBL) is a rapidly growing B-cell non-Hodgkin's lymphoma whose treatment requires highly aggressive therapies that often result severely toxic. Identification of proteins whose expression or function is deregulated in sBL and play a role in its formation could facilitate development of less toxic therapies. We have previously shown that E2F1 expression is deregulated in sBL. We have now investigated the mechanisms underlying E2F1 deregulation and found that the E2F sites in its promoter fail to repress its transcriptional activity in BL cells and that the transcriptional repressor E2F4 barely interacts with these sites. We also have found that E2F4 protein levels, but not those of its mRNA, are reduced in sBL cell lines relative to immortal B-cell lines. E2F4 protein expression is also decreased in 24 of 26 sBL tumor samples from patients compared with control tissues. Our data demonstrate that enforced E2F4 expression in BL cells not only diminishes E2F1 levels, but also reduces selectively the tumorigenic properties and proliferation of BL cells, while increasing their accumulation in G(2)/M. Our results therefore point to E2F4 as a target for developing novel and less toxic treatments for sBL.
Subject(s)
Burkitt Lymphoma/etiology , Cell Transformation, Neoplastic , E2F4 Transcription Factor/physiology , Animals , Burkitt Lymphoma/chemistry , Cell Division , Cell Line, Tumor , Cell Transformation, Neoplastic/chemistry , Crk-Associated Substrate Protein/physiology , E2F1 Transcription Factor/analysis , E2F1 Transcription Factor/genetics , E2F4 Transcription Factor/analysis , Female , G2 Phase , Humans , Mice , NIH 3T3 Cells , Promoter Regions, GeneticABSTRACT
Chlorophyllin (CHL) is a water-soluble derivative of chlorophyll that exhibits cancer chemopreventive properties, but which also has been studied for its possible cancer therapeutic effects. We report here that human colon cancer cells treated with CHL accumulate in S-phase of the cell cycle, and this is associated with reduced expression levels of p53, p21, and other G(1)/S checkpoint controls. At the same time, E2F1 and E2F4 transcription factors become elevated and exhibit increased DNA binding activity. In CHL-treated colon cancer cells, bromodeoxyuridine pulse-chase experiments provided evidence for the inhibition of DNA synthesis. Ribonucleotide reductase (RR), a pivotal enzyme for DNA synthesis and repair, was reduced at the mRNA and protein level after CHL treatment, and the enzymatic activity was inhibited in a concentration-dependent manner both in vitro and in vivo. Immunoblotting revealed that expression levels of RR subunits R1, R2, and p53R2 were reduced by CHL treatment in HCT116 (p53(+/+)) and HCT116 (p53(-/-)) cells, supporting a p53-independent mechanism. Prior studies have shown that reduced levels of RR small subunits can increase the sensitivity of colon cancer cells to clinically used DNA-damaging agents and RR inhibitors. We conclude that by inhibiting R1, R2, and p53R2, CHL has the potential to be effective in the clinical setting, when used alone or in combination with currently available cancer therapeutic agents.
