Low E2F2 activity is associated with high genomic instability and PARPi resistance

Abstract

34The E2F family, classically known for a central role in cell cycle, has a number of emerging roles 35 in cancer including angiogenesis, metabolic reprogramming, metastasis and DNA repair. E2F1 36 specifically has been shown to be a critical mediator of DNA repair; however, little is known about 37 DNA repair and other E2F family members. Here we present an integrative bioinformatic and 38 high throughput drug screening study to define the role of E2F2 in maintaining genomic integrity 39 in breast cancer. We utilized in vitro E2F2 ChIP-chip and over expression data to identify 40 transcriptional targets of E2F2. This data was integrated with gene expression from E2F2 41 knockout tumors in an MMTV-Neu background. Finally, this data was compared to human 42 datasets to identify conserved roles of E2F2 in human breast cancer through the TCGA breast 43 cancer, Cancer Cell Line Encyclopedia, and CancerRx datasets. Here we have computationally 44 predicted that E2F2 transcriptionally regulates key mediators of DNA repair. Our gene expression 45 data supports this hypothesis and low E2F2 activity is associated with a highly unstable tumor. In 46 human breast cancer E2F2, status was also correlated with a patient's response to PARP inhibition 47 therapy. Taken together this manuscript defines a novel role of E2F2 in cancer progression beyond 48 cell cycle and could be therapeutically relevant. 49 50 Author Summary 51 The E2F family of proteins have been known to regulate cell cycle and have recently been shown 52to have a number of roles in tumor progression. Here we use a combination of computational 53 techniques and high-throughput drug screening data to establish a novel role of E2F2 in 54 maintaining genomic integrity. We have shown that a number of direct and indirect target genes 55 of E2F2 are involved in multiple classical DNA repair pathways. Importantly, this was shown to 56 3 be unique to E2F2 and not present with other activator E2Fs like E2F1. We have also shown that 57 E2F2 activity is positively correlated with PARP inhibitor sensitivity regardless of BRCA1/2 58 status. This is important due to the recent approval of PARP inhibitor therapy in the clinic. Based 59 on our work E2F2 activity could serve as a novel biomarker of response and may identify a new 60 cohort of patients which could benefit from PARPi therapy. 61 62 Keywords 63 Genomic stability, breast cancer, E2F transcription factors, mouse model 64 130 ontology groups were overrepresented, including DNA repair and double-stranded break repair 131 ( Figure 1E). Given the similar pathways it was surprising that when we compared predicted E2F2 132 targets obtained through ChIP-Chip and gene expression analysis that we identified little overlap 133 in the gene lists ( Figure 1F). This may indicate that the pathways are regulated by both direct and 134 indirect / downstream targets of E2F2. To determine if there was bias towards one particular repair 135 pathway, we identified overlap between E2F2 regulated genes (gene expression and ChIP-chip) 1...

Decreased E2F2 Expression Correlates with Poor Prognosis and Immune Infiltrates in Patients with Colorectal Cancer

“…A previous study has reported that E2F2 transcriptionally accumulates in response to DNA damage, promotes Rad51 foci formation and maintains the genomic stability and integrity in neuronal cells [51]. More recently, it was reported that low E2F2 activity is correlated with high genomic instability and poor response to PARPi [52]. Notebally, it has been poorly described for the role of E2F2 in gene instability and repair in the context of cancer until now.…”