m6A regulates breast cancer proliferation and migration through stage-dependent changes in Epithelial to Mesenchymal Transition gene expression.
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2023-01
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While many factors have been implicated in breast cancer progression, effective treatments are still lacking. In recent years, it has become clear that posttranscriptional regulation plays a key role in the aberrant gene expression underlying malignancy and metastasis. For example, the mRNA modification N6-methyladenosine (m6A) is involved in numerous post-transcriptional regulation processes and has been implicated in many cancer types, including breast cancer. Despite intense study, even within a single type of cancer, there is little consensus, and often conflicting results, as to the role of m6A, suggesting other factors must influence the process. The goal of this study was to determine if the effects of m6A manipulation on proliferation and migration differed based on the stage of disease progression. Using the MCF10 model of breast cancer, we reduced m6A levels by targeting METTL3, the main cellular m6A RNA methyltransferase. Knocking down Mettl3 at different stages of breast cancer progression indeed shows unique effects at each stage. The early-stage breast cancer line showed a more proliferative phenotype with the knockdown of Mettl3 while the transformed breast cancer line showed a more migratory phenotype. Interestingly, the metastasized breast cancer cell line showed almost no effect on phenotype with the knockdown of Mettl3. Furthermore, transcriptome wide analysis revealed EMT as the probable pathway influencing the phenotypic changes. The results of this study may begin to address the controversy of m6A's role in cancer and suggest that m6A may have a dynamic role in cancer that depends on the stage of progression.
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Dorgham, Mohammed G, Brittany A Elliott, Christopher L Holley and Kyle D Mansfield (2023). m6A regulates breast cancer proliferation and migration through stage-dependent changes in Epithelial to Mesenchymal Transition gene expression. Frontiers in oncology, 13. p. 1268977. 10.3389/fonc.2023.1268977 Retrieved from https://hdl.handle.net/10161/31674.
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Scholars@Duke

Brittany Elliott
My research focuses on advancing RNA-based therapeutics and understanding the role of non-coding RNAs (ncRNAs) in disease. I am particularly passionate about translational research—bridging the gap between bench and bedside—by targeting RNAs and engineering RNA-based therapies to treat inflammatory and rare diseases.
I am also deeply interested in deciphering the mechanisms by which small nucleolar RNAs (snoRNAs) influence disease states. My current projects include exploring how RPL13a snoRNAs regulate oxidative stress, and metabolic inflammation, with the ultimate goal of developing first-in-class antisense oligonucleotide (ASO) therapeutics. I am also working on predicting, capturing, and validating novel snoRNA interactions with transcripts that could inform on their unknown functions, expanding our understanding of snoRNA biology and their potential roles in health and disease. I further aspire to expand on detection of non-coding RNAs in clinical samples and linking them to disease progression, enabling more precise diagnostic and therapeutic approaches.
Through these activities, I strive to uncover how RNA-targeting therapies can address unmet clinical needs, particularly in diseases such as atherosclerosis, chronic inflammatory disease, and others. As a scientist, I am driven by the opportunity to connect fundamental discoveries with clinical applications, and I value fostering collaboration and mentoring the next generation of researchers in RNA biology and therapeutics.
Education:
PhD University of South Carolina School of Medicine 2012
Training:
Postdoctoral Fellow Medical University of South Carolina 2013-2015
Postdoctoral Fellow Duke University 2016-2020

Christopher Lee Holley
The Holley Laboratory is focused on the role of non-coding RNA (ncRNA) in cardiovascular health and disease, with a special emphasis on snoRNA (small nucleolar RNA). snoRNAs are canonically known to guide the chemical modification of other RNAs, with ribosomal RNA being the primary target. Dr. Holley’s research has helped to uncover a novel biologic role for the Rpl13a snoRNAs in the regulation of reactive oxygen species (ROS) and oxidative stress. These four snoRNAs (U32a, U33, U34, and U35a) have a critical role in the oxidative stress response to a variety of stimuli, including saturated fatty acids, lipopolysaccharide, doxorubicin, and hydrogen peroxide.
The Holley Lab has shown that at least one mechanism linking the Rpl13a snoRNAs to ROS and oxidative stress is snoRNA-guided methylation of mRNA. This methylation in an mRNA coding sequence inhibits subsequent protein translation. We have also shown that snoRNA-guided methylation alters RNA conformational ensembles, which can stabilize short-lived structures.
Currently, the lab is studying the role of Rpl13a snoRNAs in atherosclerosis, where loss or inhibition of these snoRNAs reduces athero by ~50%. We are actively pursuing translational research opportunities to design "RNA therapeutics" targeting these snoRNAs for potential clinical use.
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