Rennhack, J. | bioRxiv Science

bioRxiv2019

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

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. Here we have computationally predicted that E2F2 transcriptionally regulates key 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 patients response to PARP inhibition therapy. Taken together this manuscript defines a novel role of E2F2 in cancer progression beyond cell cycle and could be therapeutically relevant.\n\nAuthor SummaryThe E2F family of proteins have been known to regulate cell cycle and have recently been shown to have a number of roles in tumor progression. Here we use a combination of computational techniques and high-throughput drug screening data to establish a novel role of E2F2 in maintaining genomic integrity. We have shown that a number of direct and indirect target genes of E2F2 are involved in multiple classical DNA repair pathways. Importantly, this was shown to be unique to E2F2 and not present with other activator E2Fs like E2F1. We have also shown that E2F2 activity is positively correlated with PARP inhibitor sensitivity regardless of BRCA1/2 status. This is important due to the recent approval of PARP inhibitor therapy in the clinic. Based on our work E2F2 activity could serve as a novel biomarker of response and may identify a new cohort of patients which could benefit from PARPi therapy.

cancer biology↗

bioRxiv2018

Integrated sequence and gene expression analysis of mouse models of breast cancer reveals critical events with human parallels

Mouse models have an essential role in cancer research, yet little is known about how various models resemble human cancer at a genomic level. However, the shared genomic alterations in each model and corresponding human cancer are critical for translating findings in mice to the clinic. We have completed whole genome sequencing and transcriptome profiling of two widely used mouse models of breast cancer, MMTV-Neu and MMTV-PyMT. This genomic information was integrated with phenotypic data and CRISPR/Cas9 studies to understand the impact of key events on tumor biology. Despite the engineered initiating transgenic event in these mouse models, they contain similar copy number alterations, single nucleotide variants, and translocation events as human breast cancer. Through integrative in vitro and in vivo studies, we identified copy number alterations in key extracellular matrix proteins including Collagen 1 Type 1 alpha 1 (Col1a1) and Chondroadherin (CHAD) that drive metastasis in these mouse models. Importantly this amplification is also found in 25% of HER2+ human breast cancer and is associated with increased metastasis. In addition to copy number alterations, we observed a propensity of the tumors to modulate tyrosine kinase mediated signaling through mutation of phosphatases. Specifically, we found that 81% of MMTV-PyMT tumors have a mutation in the EGFR regulatory phosphatase, PTPRH. Mutation in PTPRH led to increased phospho-EGFR levels and decreased latency. Moreover, PTPRH mutations increased response to EGFR kinase inhibitors. Analogous PTPRH mutations are present in lung cancer patients and together this data suggests that a previously unidentified population of human lung cancer patients may respond to EGFR targeted therapy. These findings underscore the importance of understanding the complete genomic landscape of a mouse model and illustrate the utility this has in understanding human cancers.

cancer biology↗