publications

2023

1. 

   Integrative multi-omic sequencing reveals the MMTV-Myc mouse model mimics human breast cancer heterogeneity

   Carson D. Broeker ,  Mylena M. O. Ortiz ,  Michael S. Murillo ,  and  Eran R. Andrechek

   Breast Cancer Research, Oct 2023

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   Breast cancer is a complex and heterogeneous disease with distinct subtypes and molecular profiles corresponding to different clinical outcomes. Mouse models of breast cancer are widely used, but their relevance in capturing the heterogeneity of human disease is unclear. Previous studies have shown the heterogeneity at the gene expression level for the MMTV-Myc model, but have only speculated on the underlying genetics.

2022

1. 

   E2F Transcription Factors in Cancer, More than the Cell Cycle

   Carson D. Broeker ,  and  Eran R. Andrechek

   In Comprehensive Pharmacology , Jan 2022

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   In the 1980s, research groups set out to identify the protein that could bind the adenovirus E2 promoter, already known to be inducible by the adenovirus E1A gene product. Joseph Nevins’ group found through gel-shift assays, DNA footprinting, and competition assays that an intrinsic cellular factor similar to E1A could bind the E2 adenoviral promoter. The first of the E2F transcription factors to be identified was E2F1, copurified with antibodies against the retinoblastoma protein (pRB). RB1 is a pocket protein and tumor suppressor known predominantly for its critical role in regulating the G1 to S-phase cell cycle entry, accomplished through sequestering E2F until phosphorylated via cyclin-dependent kinases. Other experiments showing adenovirus E1A protein could compete for pRB complexing further confirmed that pRB was a specific target of E2F transcription factors. Along with many promoters found to contain consensus sequences for E2F binding, E2F1 was later shown to induce S-phase cell cycle genes responsible for DNA synthesis, release gamma irradiated cells from G1 arrest, and, when overexpressed, induce apoptosis. Currently a total of eight E2F transcription factors have been identified, all binding to a similar consensus motif of TTTSSCGC, with S being either a G or a C in this instance. However, microarray analyses and chromatin immunoprecipitation-chip (ChIP-chip) studies have provided evidence that E2Fs can be recruited to non-consensus binding sites on core promoter regions and that many E2Fs are both degenerate in their functions and can compensate for each other. E2Fs have been grouped together based on their conserved DNA binding domains and have garnered attention for both their first identified role as integral in driving the cell cycle but gained prominence for noncanonical roles including apoptosis, DNA repair, and others. Many of these functions, both canonical and noncanonical, are important in the induction of carcinogenesis.

2. 

   Large-Scale SARS-CoV-2 Testing Utilizing Saliva and Transposition Sample Pooling

   Joseph R. Patterson ,  Allyson Cole-Strauss ,  Nathan Kuhn ,  Carlene Mercier ,  Joseph Kochmanski ,  John A. Gerlach ,  Rhiannon M. LeVeque ,  Kerri A. Neugebauer ,  Kayla N. Conner ,  Jasper Gomez ,  Mark G. Hennes ,  Kaje’ne E. Thompson ,  Destinee L. Rytlewski ,  Chloe C. Bigwood ,  Amy Scharmen ,  Gabriel Simjanovski ,  Cassidy Riley ,  Jessica Donaldson ,  Dilann Yasin ,  Najwa Kouja ,  Zaria Contejean ,  Michaela Burnett ,  Shakhlo Aminova ,  Nat Ato Yawson ,  Simran B. Singh ,  Osama M. Alian ,  Carson D. Broeker ,  Erin K. Zaluzec ,  Morgan ONeill ,  Birgit Puschner ,  Aron Sousa ,  Laura Bix ,  Brian Jespersen ,  Claudia Holzman ,  Jade Mitchell ,  Ryan Julien ,  Yesim Askin ,  Danielle Barnes ,  Purna Durshanpalli ,  Doug Krum ,  Rett Weber ,  Morgan Patterson ,  Becky Anderson ,  Ryan Hunt ,  Benjamin O’Brien ,  Andrew Umstead ,  John S. Beck ,  Irving E. Vega ,  Caryl E. Sortwell ,  and  Jack W. Lipton

   JoVE (Journal of Visualized Experiments), Jan 2022

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   Identification and isolation of contagious individuals along with quarantine of close contacts, is critical for slowing the spread of COVID-19. Large-scale testing in a surveillance or screening capacity for asymptomatic carriers of COVID-19 provides both data on viral spread and the follow-up ability to rapidly test individuals during suspected outbreaks. The COVID-19 early detection program at Michigan State University has been utilizing large-scale testing in a surveillance or screening capacity since fall of 2020. The methods adapted here take advantage of the reliability, large sample volume, and self-collection benefits of saliva, paired with a cost-effective, reagent conserving two-dimensional pooling scheme. The process was designed to be adaptable to supply shortages, with many components of the kits and the assay easily substituted. The processes outlined for collecting and processing SARS-CoV-2 samples can be adapted to test for future viral pathogens reliably expressed in saliva. By providing this blueprint for universities or other organizations, preparedness plans for future viral outbreaks can be developed.

2021

1. 

   Insight into mammary gland development and tumor prevention in a newly developed metastatic mouse model of breast cancer

   Briana To ,  Carson Broeker ,  Jing-Ru Jhan ,  Rachel Rempel ,  Jonathan P. Rennhack ,  Daniel Hollern ,  Lauren Jackson ,  David Judah ,  Matt Swiatnicki ,  Evan Bylett ,  Rachel Kubiak ,  Jordan Honeysett ,  Reaz Shams ,  Joseph Nevins ,  and  Eran Andrechek

   bioRxiv, Jan 2021

   Publisher: Cold Spring Harbor Laboratory

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   The development of breast cancer has been observed due to altered regulation of mammary gland developmental processes. Thus, a better understand of the normal mammary gland development can reveal possible mechanism in how normal cells are re-programmed to become malignant cells. E2F1-4 are part of the E2F transcription factor family with varied roles in mammary development. However, little is known about the role of E2F5 in mammary gland development. A combination of scRNAseq and predictive signature tools demonstrate the presence of E2F5 in the mammary gland and showed altered activity during the various phases of mammary gland development and function. Testing the hypothesis that E2F5 regulates mammary function, we generated a mammary-specific E2F5 knockout mouse model, resulting in modest mammary gland development changes. However, after a prolonged latency the E2F5 conditional knockout mice developed highly metastatic mammary tumors with metastases in both the lung and liver. Transplantation of the tumors revealed metastases to lymph nodes that was enriched through serial transplantation. Through whole genome sequencing and RNAseq analysis we identified, and then confirmed in vivo, that Cyclin D1 was dysregulated in E2F5 conditional knockout mammary glands and tumors. Based on these findings, we propose that loss of E2F5 leads altered regulation of Cyclin D1, which facilitates the development of mammary tumors.