Alexandra Nail, Ph.D.

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Dr. Alexandra Nail is a NIH K99/R00 Pathway to Independence Award recipient from the National Institute of Environmental Health Sciences (NIEHS). She currently works in the laboratory of Dr. J. Christopher States; her work focuses on understanding how environmental exposure to heavy metals, specifically cadmium, promote triple-negative breast cancer by disruption of DNA double-strand break repair and signaling. Dr. Nail is aiming to start a tenure-track faculty position by July 2026.

Prior to her work on cadmium and breast cancer, Dr. Nail was funded by the American Cancer Society (ACS). Her ACS postdoctoral fellowship work focused on elucidating whether heavy metal exposure promoted skin and lung cancers by disruption of DNA double-strand break repair and signaling. Before her work as an ACS postdoctoral fellow, Dr. Nail received funding from the University of Louisville NIEHS T32 Training Program in environmental health sciences.She earned her PhD in Microbiology from the University of Kentucky in 2019; her dissertation work focused on determining post-transcriptional regulation of sex-dependent genes in the liver and determining when gene expansions occurred during chordate evolution. Dr. Nail is originally from Montana and received her MS and BS degrees from Morehead State University where she received a full-ride athletic scholarship to play Division 1 softball as a pitcher (maiden name Gjevre).

Dr. Nail’s research interests and goals include:

  • Environmental Carcinogens & Cancer Risk – Investigating how pollutants and environmental toxins promote breast cancer by genetic or epigenetic changes
  • Molecular Mechanisms of Cancer Progression – Determining how specific molecular pathways are affected by environmental exposures and how that impacts breast cancer initiation or metastasis
  • Prevention & Early Detection – Exploring biomarkers linked to environmental exposure and cancer risk, potentially leading to better screening tools
  • Therapeutic Approaches – Examining how molecular biology can inform treatments, especially targeting environmentally-driven pathogenic mutations

Click here to view Dr. Nail's CV

Double-strand breaks in the DNA duplex can lead to irreversible genetic loss and various forms of improper repair in a cell. Improper repair of DNA double-strand breaks can cause genomic instability such as gene mutations and deletions. Genomic instability is a hallmark of cancer, and it can serve as the first step in cancer development and contributes to cancer progression. I am interested in understanding the cellular mechanisms that govern DNA double-strand break repair and how environmental exposure to heavy metals disrupts these normal repair processes.

Cancer caused by environmental heavy metal pollution is one of the major challenges faced by modern society. Rapid industrialization over the past century has played a major role in elevating heavy metal exposure risk for the general population. Heavy metal pollution is increased by industrial activities such as mineral resources extraction, metal processing and smelting, chemical production, factory emissions, and sewage irrigation.

Targeting of the MRN Complex by Heavy Metals

We recently demonstrated that long-term, low-dose exposure to heavy metals (inorganic arsenic and cadmium) interferes with key DNA damage response pathways. However, these metals act at common and different points within the DNA damage response to promote genomic instability. Whereas skin keratinocytes exposed long-term to inorganic arsenic display inhibited ataxia telengectasia protein mutated (ATM) phosphorylation normally mediated by the MRE11/RAD50/NBN (MRN) complex, ATM phosphorylation is not higher in breast epithelial cells exposed chronically to cadmium. These results suggest that Cd may prevent further ATM activation in cells with Cd-induced DSB accumulation. The MRN complex is an evolutionarily conserved molecular machine responsible for processing DNA ends, bringing broken strands together, and signaling the presence of damage within the cell. A key question is whether MRN complex function is inhibited by exposure to either metal. To address this question, we are utilizing proteomics and single-molecule-based imaging techniques with recombinant MRN complex proteins to determine whether either metal can displace zinc from RAD50, and, whether the MRN complex can bind to DNA after inorganic arsenic or cadmium exposure.

Does cadmium exposure drive triple-negative breast cancer initiation and progression by mimicking homologous recombination deficiencies?

Individuals with BReast CAncer 1 (BRCA1) germline mutations (BRCA1+/-) have an increased risk of developing breast cancer, notably triple-negative breast cancers, compared to individuals without BRCA1 germline mutations. However, genetic predisposition is absent in the large majority (~80%) of breast cancers, suggesting that environmental factors may be a major driver of breast cancer susceptibility. Breast epithelial cells are malignantly transformed by cadmium after 40 weeks of exposure. Recently, we found that only 8 weeks of cadmium exposure inhibits BRCA1 phosphorylation mediated by ATM and Ataxia telengectasia-related (ATR) tyrosine kinases in breast epithelial cells with normal BRCA1. These data suggest that long-term cadmium exposure mimics BRCA1 deficiency normally seen in individuals with BRCA1 germline mutations. However, it is unclear how this inhibition is occuring. Does cadmium bind to BRCA1, displace zinc, and lock the protein in a confirmation that prevents its normal activation by ATM or ATR? We are beginning to address this question using proteomics and CRISPR-based DNA repair assays to determine whether BRCA1 function is compromised by cadmium exposure.

Summary of ongoing projects. Cadmium (Cd) and inorganic arsenic (iAs) are known to promote DNA double-strand break accumulation in human cells. iAs is known to inhibit Ataxia mutated telengectasia (ATM) autophosphorylation (pSer1981) and downstream Checkpoint Kinase 2 (CHEK2) phosphorylation (pThr68). Our recent work demonstrates that Cd may also inhibit the MRN complex by preventing further ATM-pSer1981 phosphorylation. Proteomics and single-molecule-based imaging techniques are being used to determine how heavy metal exposure may disrupt MRN function. Chronic Cd exposure inhibits BRCA1 phosphorylation (pSer1524) that is mediated by ATM and ATR Serine/Threonine Kinase (ATR). However, ATM and ATR do not rely on zinc for their function and are therefore not hypothesized to be directly targeted by Cd. BRCA1 is a protein that relies on zinc for its function. Proteomics and CRISPR-based DNA repair assays, and additional experiments, are being used to determine whether BRCA1 function is impaired in breast epithelial cells exposed long-term to Cd. Additional experiments are underway to determine how Cd may also directly inhibit Tumor Protein 53 (TP53) function.

NIEHS K99/R00 Pathway to Independence Career Transition Award (K99ES036286): Unraveling the molecular link between heavy metal exposure and triple-negative breast cancer

American Cancer Society Postdoctoral Fellowship (relinquished in August 2024 to commence K99/R00 Career Transition Award) (PF-23-1153675): Diminished DNA Damage Signaling as a Driver of Heavy Metal-Induced Genomic Instability and Carcinogenesis

University of Louisville T32 Training Program Postdoctoral Fellow

ALL

  1. Total Citations: 185
  2. H-Index: 6
  3. ¡10-Index: 3

Since 2020

  1. Total Citations: 179
  2. H-Index: 6
  3. ¡10-Index: 3
  4. Nail A.N. , Chavez A.V., Bailey A.N., Banerjee M., Scott J.L., Thomas S.D., States J.C (2025). DNA Damage Response Inhibition is an Early Event in Cadmium-Induced Breast Carcinogenesis. Toxicology and Applied Pharmacology (Under Review).
  5. Tomlinson M.M., Pugh F., Nail A.N., Newton J.D., Udoh K., Abraham S., Kavalukas S., Guinn B., Tamimi R.M., Laden F., Iyer H., States J.C., Ruther M., Ellis C.T., Dupré N.C. (2024). Heavy-Metal Associated Breast Cancer and Colorectal Cancer Hot Spots and their Demographic and Socioeconomic Characteristics. Cancer Causes & Control. 35(10):1367-1381. DOI: 10.1007/s10552-024-01894-0
  6. Augenstein I., Nail A.N., Ferragut Cardoso A.P., States J.C., & Banerjee M. (2024). Chronic arsenic exposure suppresses proteosomal and autophagic protein degradation. Environmental Toxicology and Pharmacology, 107:104398. DOI: 10.1016/j.etap.2024.104398
  7. Nail A.N., Xu M., Bastick J.C., Patel D.P., Rogers M.N., & States J.C. (2023). Arsenic and Human Health: New Molecular Mechanisms for Arsenic-Induced Cancer. Current Pollution Reports. 9:784-797. DOI: https://doi.org/10.1007/s40726-023-00278-3
  8. Ferragut Cardoso A. P., Nail A. N., Banerjee M., Wise S. S., & States, J. C. (2023). miR-186 induces tetraploidy in arsenic exposed human keratinocytes. Ecotoxicology and environmental safety, 256: 114823. DOI:10.1016/j.ecoenv.2023.114823
  9. Nail A.N., Ferragut Cardoso A.P., Montero L.M., & States J.C. (2023). miRNAs and arsenic-induced carcinogenesis. Advances in Pharmacology. 96, 203–240. DOI: 10.1016/bs.apha.2022.10.002
  10. Schweer D., Anand N., Anderson A., McCorkle J.R., Neupane K., Nail A.N., Harvey B., Hill K.S., Ueland F., Richards C., & Kolesar J. (2023) Human macrophage-engineered vesicles for utilization in ovarian cancer treatment. Front Oncol. 12:1042730. DOI: 10.3389/fonc.2022.1042730
  11. Nail A.N., Ferragut Cardoso A.P., Banerjee M. & States J.C. (2022). Circulating miRNAs as Biomarkers of Toxic Heavy Metal Exposure. In Genomic and Epigenomic Biomarkers of Toxicology and Disease, S.C. Sahu (Ed.). DOI:10.1002/9781119807704.ch4
  12. Nail A.N., McCaffrey L.M., Banerjee M., Ferragut Cardoso A.P., & States J.C. (2022) Chronic arsenic exposure suppresses ATM pathway activation in human keratinocytes. Toxicology and Applied Pharmacology. 446:116042. DOI: 10.1016/j.taap.2022.116042
  13. Ferragut Cardoso A.P., Banerjee M., Nail A.N., Lykoudi A., & States J.C. (2021). miRNA dysregulation is an emerging modulator of genomic instability. Seminars in Cancer Biology. 76: 120-131. DOI: 10.1016/j.semcancer.2021.05.004
  14. Nail A.N. , Spear B.T., & Peterson M.L. (2020). Highly homologous mouse Cyp2a4 and Cyp2a5 genes are differentially expressed in the liver and both express long non-coding antisense RNAs. Gene. 767(30). DOI: 10.1016/j.gene.2020.145162
  15. Nail A.N., Smith J.J., Peterson M.L., & Spear B.T. (2020). Evolutionary Analysis of the Zinc Finger and Homeoboxes Family of Proteins Identifies Multiple Conserved Domains and a Common Early Chordate Ancestor. Genome Biology and Evolution. 12(3):174-184. DOI: 10.1093/gbe/evaa039
  16. Savage C., Arnold W., Gjevre-Nail A., Koestler B., Bruger E., Barker J., Waters C., & Stevenson B. (2015). Intracellular concentrations of borrelia burgdorferi cyclic di-amp are not changed by altered expression of the cdaA synthase. PLoS ONE. 10(4). DOI: 10.1371/journal.pone.0125440