Baker Institute for Animal Health
235 Hungerford Hill Road
Ithaca, NY 14853
Office: (607) 256-5657
Fax: (607) 256-5608
Cancer is the out of control growth of abnormal cells in the body, and it is known to strike almost every species of animal, including dogs, cats, horses, and, of course, humans. The special focus in Dr. Scott Coonrod’s lab is breast cancer, referred to as “mammary cancer” in animals. Dr. Coonrod, who is the Judy Wilpon Associate Professor of Cancer Biology, is searching for ways to stop breast cancer cells from developing by specifically turning off genes in the cancer cells that are required for cell growth.
The genes encoded on a strand of deoxyribonucleic acid (DNA) represent blueprints for how to make the myriad proteins a cell needs. If stretched out from end to end, the DNA from a single human or animal cell would stretch two meters long, so the cell keeps DNA organized and compacted by wrapping it around a series of hockey puck-shaped proteins called histones, forming a strand of chromatin that resembles a string of beads. Epigenetic modifications to the puck-shaped histones or to the genes themselves mark the genes according to how much that particular protein will be needed to keep the cell functioning properly, targeting the gene/protein for greater or lesser production as necessary. In cancerous cells these signals are flawed, triggering the cells to make disproportionate amounts of certain growth-related proteins, leading to out of control growth, disrupting the normal functions of the tissue, and putting the animal’s life at risk.
The Coonrod lab is currently focused on a small family of enzymes called PAD that apply these signals, or “marks”, to histones. Dr. Coonrod recently found that one member of the PAD family, PAD2, makes histone modifications that impact the expression of genes that are regulated by the estrogen receptor. Increased estrogen receptor activity is thought to cause up to 75% of all breast cancers and is, therefore, a major target for breast cancer therapies. The Coonrod lab found that PAD2 marks histones at estrogen receptor binding sites and that this novel mark appears to be required for estrogen receptor binding and target gene activation. Hence, the ability of the estrogen receptor to bind to genes where PAD2 makes its mark on the histones is an important factor that may promote breast cancer progression.
Dr. Coonrod has found that blocking PAD2 and the epigenetic changes it makes prevents the estrogen receptor from binding to the relevant genes and prevents estrogen receptor positive breast cancer cells from dividing. This makes PAD2 a very promising target for treating breast cancer, so Dr. Coonrod and his lab are investigating ways to stop the spread of cancer by shutting down PAD2.
Dr. Coonrod’s work has the potential to uncover some powerful new ways for treating breast cancer – and preventing its return. Breast cancer survivors today who are at high risk for recurrence are administered the drug tamoxifen for years following their diagnosis and treatment, but most women become resistant to this adjuvant therapy within five years. PAD2 inhibitors could represent a potent new therapy for these women who are no longer responsive to tamoxifen therapy. Given that most cases of mammary cancer in canines are estrogen receptor positive, Dr. Coonrod hopes that, once developed, PAD2 inhibitors will also represent a new therapeutic option for canine mammary cancer.
1. Lewallen, DM; Bicker, KL; Madoux, F; Chase, P; Anguish, L; Coonrod, S; Hodder, P; Thompson, PR. (2014). A FluoPol-ABPP PAD2 High-Throughput Screen Identifies the First Calcium Site Inhibitor Targeting the PADs. ACS Chemical Biology, 18;9(4):913-21. Abstract.
2. Kim, B; Zhang, XS; Kan, R; Cohen, R; Mukai, C; Travis, AJ; Coonrod, SA. (2014). The role of MATER in endoplasmic reticulum distribution and calcium homeostasis in mouse oocytes. Developmental Biology, 15;386(2):331-9. Abstract.
3. Stadler, SC; Vincent, CT; Fedorov, VD; Patsialou, A; Cherrington, BD; Wakshlag, JJ; Mohanan, S; Zee, BM; Zhang, XS; Garcia, BA; Condeelis, JS; Brown, AMC; Coonrod, SA; Allis, CD. (2013). Dysregulation of PAD4-mediated citrullination of nuclear GSK3 beta activates TGF-beta signaling and induces epithelial-to-mesenchymal transition in breast cancer cells. Proceedings of the National Academy of Sciences of the United States of America, 110(29): 11851–11856.
4. Mohanan S, Horibata S, McElwee JL, Dannenberg AJ, Coonrod SA. (2013) Identification of macrophage extracellular trap-like structures in mammary gland adipose tissue: a preliminary study. Frontiers in Immunology 18;4:67. Pdf Mohanan Frontiers Imm 2013
5. Clark, PA; Xie, JJ; Li, S; Zhang, XS; Coonrod, S; Roberson, MS. (2013). Matrix metalloproteinase 9 is a distal-less 3 target-gene in placental trophoblast cells. American Journal of Physiology – Cell Physiology. Abstract.
6. Bicker, KL; Anguish, L; Chumanevich, AA; Cameron, MD; Cui, XL; Witalison, E; Subramanian, V; Zhang, XS; Chumanevich, AP; Hofseth, LJ; Coonrod, SA; Thompson, PR. (2012). D-Amino Acid-Based Protein Arginine Deiminase Inhibitors: Synthesis, Pharmacokinetics, and in Cellulo Efficacy. ACS Medicinal Chemistry Letters, 26;3(12):1081-1085. Abstract.
7. McElwee, JL; Mohanan, S; Griffith, OL; Breuer, HC; Anguish, LJ; Cherrington, BD; Palmer, AM; Howe, LR; Subramanian, V; Causey, CP; Thompson, PR; Gray, JW; Coonrod, SA. (2012) Identification of PADI2 as a potential breast cancer biomarker and therapeutic target. BMC Cancer, 12:500.
9. Zhang, XS; Bolt, M; Guertin, MJ; Chen, W; Zhang, S; Cherrington, BD; Slade, DJ; Dreyton, CJ; Subramanian, V; Bicker, KL; Thompson, PR; Mancini, MA; Lis, JT; Coonrod, SA. (2012). Peptidylarginine deiminase 2-catalyzed histone H3 arginine 26 citrullination facilitates estrogen receptor alpha target gene activation. Proceedings of the National Academy of Sciences of the United States of America, 14;109(33):13331-6.
10. Cherrington, BD; Mohanan, S; Diep, AN; Fleiss, R; Sudilovsky, D; Anguish, LJ; Coonrod, SA; Wakshlag, JJ. (2012). Comparative Analysis of Peptidylarginine Deiminase-2 Expression in Canine, Feline and Human Mammary Tumours. Journal of Comparative Pathology, 147(2-3):139-46. Abstract.
11. Cherrington, BD; Zhang, XS; McElwee, JL; Morency, E; Anguish, LJ; Coonrod, SA. (2012) Potential Role for PAD2 in Gene Regulation in Breast Cancer Cells. PLOS One, 7(7):e41242.
12. Kan, R; Jin, M; Subramanian, V; Causey, CP; Thompson, PR; Coonrod, SA. (2012) Potential role for PADI-mediated histone citrullination in preimplantation development. BMC Developmental Biology, 12:19.
13. Horibata S, Coonrod SA, Cherrington BD. (2012) Role for peptidylarginine deiminase enzymes in disease and female reproduction. Journal of Reproduction and Development, 58(3):274-82. Abstract.
14. Mohanan S, Cherrington BD, Horibata S, McElwee JL, Thompson PR, Coonrod SA. (2012) Potential role of peptidylarginine deiminase enzymes and protein citrullination in cancer pathogenesis. Epub 2012 Sep 16. Download pdf. Mohanan BRI Review 2012
15. Zhang X, Gamble MJ, Stadler S, Cherrington BD, Causey CP, Thompson PR, Roberson MS, Kraus WL, Coonrod SA. (2011) Genome-wide analysis reveals PADI4 cooperates with Elk-1 to activate c-Fos expression in breast cancer cells. PLoS Genetics 7(6):e1002112.
16. Wang Y, Li M, Stadler S, Correll S, Li P, Wang D, Hayama R, Leonelli L, Han H, Grigoryev SA, Allis CD, Coonrod SA. (2009) Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation. Journal of Cell Biology 26;184(2):205-13.
17. Wang Y, Wysocka J, Sayegh J, Lee YH, Perlin JR, Leonelli L, Sonbuchner LS, McDonald CH, Cook RG, Dou Y, Roeder RG, Clarke S, Stallcup MR, Allis CD, Coonrod SA. (2004) Human PAD4 regulates histone arginine methylation levels via demethylimination. Science, 306(5694):279-83.