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Low E2F2 activity is associated with high genomic instability and PARPi resistance
Jonathan P Rennhack1, Eran R Andrechek2,3
1Department of Physiology, Michigan State University, East Lansing, MI, USA.
Abstract:
The E2F family, classically known for a central role in cell cycle, has a number of emerging roles in cancer including angiogenesis, metabolic reprogramming, metastasis and DNA repair. E2F1 specifically has been shown to be a critical mediator of DNA repair; however, little is known about DNA repair and other E2F family members. Here we present an integrative bioinformatic and high throughput drug screening study to define the role of E2F2 in maintaining genomic integrity in breast cancer. We utilized in vitro E2F2 ChIP-chip and over expression data to identify transcriptional targets of E2F2. This data was integrated with gene expression from E2F2 knockout tumors in an MMTV-Neu background. Finally, this data was compared to human datasets to identify conserved roles of E2F2 in human breast cancer through the TCGA breast cancer, Cancer Cell Line Encyclopedia, and CancerRx datasets. Through these methods we predict that E2F2 transcriptionally regulates mediators of DNA repair. Our gene expression data supports this hypothesis and low E2F2 activity is associated with a highly unstable tumor. In human breast cancer E2F2, status was also correlated with a patient's response to PARP inhibition therapy. Taken together this manuscript defines a novel role of E2F2 in cancer progression beyond cell cycle and could impact patient treatment.
Insights
This study reveals that E2F2 plays a crucial role in maintaining genomic integrity in breast cancer by regulating DNA repair. Lower E2F2 activity correlates with tumor instability and impacts patient response to PARP inhibitors.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- The E2F family of transcription factors is known for its role in cell cycle regulation.
- Emerging evidence suggests diverse roles for E2F family members in cancer, including DNA repair.
- The specific function of E2F2 in maintaining genomic integrity in breast cancer remains largely undefined.
Purpose of the Study:
- To define the role of E2F2 in maintaining genomic integrity in breast cancer.
- To identify transcriptional targets of E2F2 involved in DNA repair.
- To investigate the clinical relevance of E2F2 status in human breast cancer.
Main Methods:
- Integrative bioinformatic analysis of E2F2 ChIP-chip and gene expression data.
- Utilized E2F2 knockout mouse models (MMTV-Neu background).
- Compared findings with human datasets including TCGA, Cancer Cell Line Encyclopedia, and CancerRx.
Main Results:
- E2F2 was predicted to transcriptionally regulate DNA repair mediators.
- Gene expression data supported E2F2's role in DNA repair, with low E2F2 activity linked to tumor instability.
- E2F2 status in human breast cancer correlated with patient response to PARP inhibition therapy.
Conclusions:
- E2F2 has a novel role in breast cancer progression beyond cell cycle control.
- E2F2's regulation of DNA repair is critical for genomic stability.
- Understanding E2F2 function may impact therapeutic strategies for breast cancer patients, particularly those treated with PARP inhibitors.
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