Page 45 - Hormel Institute Annual Report 2021-22
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 promotes tumor growth and progression, concurrent with increased H3K9 methylation. To test this hypoth- esis, we have established both cell culture models and transgenic mouse models that will allow us to decipher how HR loss promotes BC development. Additionally, we will test a novel class of drugs target- ing aberrant histone methylation pathways (epigen- etic drugs) as new, attractive treatment options to abrogate breast tumor growth and progression by targeting HR-dependent epigenetic defects. We expect these studies will have a positive impact by uncovering novel genetic and epigenetic determi- nants of BC pathogenesis, which will significantly facilitate the development of mechanism-based biomarkers and epigenetic and/or targeted therapies to improve patient survival and quality of life.
Targeting the TXNIP-PRDX6 redox signaling pathway for pro-oxidant cancer therapy Compared to healthy cells, cancer cells produce higher levels of reactive oxygen species (ROS) due to increased metabolic and mitochondrial activity. To maintain redox homeostasis, cancer cells upregulate their ROS scavengers including the thioredoxin (TXN) and peroxiredoxin (PRDX) proteins to survive high oxidative stress. The distinctive features of oxida- tive metabolism between cancer and healthy cells provides an opportunity to develop cancer-specific therapies by targeting redox homeostasis. Thiore- doxin-interacting protein (TXNIP) plays a major role in ROS signaling through inhibiting TXN activity. TXNIP is down-regulated in human cancers, and its down-regulation in breast cancer (BC) correlates with reduced overall survival. By using a proteomic approach, we identified PRDX6 as a novel TXNIP-in- teracting protein. Among PRDX family antioxidant proteins, PRDX6 is unique in that it can reduce both H2O2 and short chain phospholipid hydroperoxides. Prdx6-knockout mice are viable and healthy, indicating that it is dispensable for normal cell
function. While TXNIP is down-regulated in BC, PRDX6 expression is often elevated and associated with poor overall survival in BC patients. However, the function and mechanism of PRDX6 dysregulation in BC pathogenesis is not well understood. In this project, we will study the role of the TXNIP-PRDX6 redox system in BC pathogenesis and explore its potential as a target for developing pro-oxidant BC therapies. Our hypothesis is that TXNIP suppresses PRDX6’s antioxidant activity, leading to increased ROS levels to impair BC cell proliferation and survival. We will define the role of TXNIP-PRDX6 redox system in regulating BC growth and progression using both cell culture and mouse models. Furthermore, we will investigate the anticancer efficacy of PRDX6 inhi- bition in combination with epigenetic activation of TXNIP in preclinical BC models.
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  Role of hairless and its target gene CELF2 in tumorigenesis and cancer drug resistance Despite decades of research, significant gaps remain in our knowledge of how breast cancer (BC) develops. This project is based on our previous studies that have identified a new candidate BC risk gene hairless (HR). In addition to HR’s function in the skin, we recently showed that mice with a defective HR gene are at an increased risk of developing cancer. We also found that HR is frequently mutated or lost in human BCs especially in aggressive and life- threatening BC subtypes. The overall objective of this project is to define HR’s role in BC pathogenesis. Our guiding hypothesis is that HR is a novel tumor suppressor gene in mammary tissue whose loss
Recent Publication:
• Shen, Y., Singh, J., Sah, B., Chen, Z., Ha, W., Henzler, C., Su, T., Xie, L., Deng, Y., Li, G.,
Guo, H., Hibshoosh, H., & Liu, L. (2022). The Histone Demethylase HR Suppresses Breast Cancer Development through Enhanced CELF2 Tumor Suppressor Activity. Cancers (Basel), 14(19), 4684.
• Trager, M. H., Sah, B., Chen, Z., & Liu, L. (2021). Control of Breast Cancer Pathogenesis
by Histone Methylation and the Hairless Histone Demethylase. Endocrinology, 162(8), 1-15.
• Queen, D., Shen, Y., Trager, M. H., Lopez, A. T., Samie, F. H., Lewin, J. M., Niedt, G. W., Geskin, L. J., & Liu, L. (2020). UV biomarker genes for classification and risk stratification of cutaneous actinic keratoses and squamous cell carcinoma subtypes. Faseb j, 34(9), 13022-13032.
ORCID iD: https://orcid.org/0000-0001-7245-355X























































































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