Page 45 - Hormel Report 2023

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TXNIP binds to CAST to inhibit its tumor-promoting activity, thereby impairing breast cancer cell prolifera- tion, survival, and in vivo tumor growth. Furthermore, we will delve into how CAST promotes breast cancer cell proliferation and tumor growth. In parallel, we
will explore the TXNIP-IL24-STAT3 signaling axis
in breast cancer growth and survival. IL24 exhibits broad, tumor-specific tumor-suppressive properties, while STAT3 is a transcription activator promoting cancer growth and progression. We have data sug- gesting TXNIP upregulates IL24 in MDA-MB-231 and HER2+ HCC1954 breast cancer cells, concomitant with reduced STAT3 activation. Therefore, we will test the hypothesis that TXNIP impairs breast cancer cell growth and survival by activating IL24 and suppress- ing STAT3 signaling. Additionally, we will explore the potential synergistic effects between IL24 treatment and STAT3 inhibition in vitro and their capacity to inhibit breast cancer cell proliferation and suppress tumor growth in vivo.
Role of Hairless and Its Target Gene CELF2 in Tumorigenesis and Cancer Drug Resistance
This project is based on our recent studies that
have identified a new candidate risk gene, known as “hairless” (HR), in relation to breast cancer. In addition to HR’s well-characterized function in the skin and hair follicle biology, we recently demonstrated that mice with a faulty HR gene exhibit an elevated sus- ceptibility to cancer. Furthermore, we found a high prevalence of HR mutations or loss in human breast cancers, particularly in the more aggressive and life-threatening subtypes.
The overarching goal of this project is to elucidate the role of HR in the pathogenesis of breast cancer. Our central hypothesis posits that HR functions as a previously unknown tumor suppressor gene within mammary tissue. Its absence, we believe, promotes tumor initiation and progression, concurrent with an increase in H3K9 methylation. To rigorously examine this hypothesis, we have established both cell culture models and transgenic mouse models that will en- able us to investigate how HR loss promotes breast cancer development. Additionally, we will explore
a novel class of drugs that target aberrant histone methylation pathways, termed epigenetic drugs, as promising new treatment options to thwart breast tumor growth and progression, particularly by target- ing HR-dependent epigenetic abnormalities. These studies could make a positive impact on our under- standing of breast cancer by shedding light on novel genetic and epigenetic factors involved in breast cancer pathogenesis. This, in turn, will significantly enhance the development of mechanism-based bio- markers and targeted therapies aimed at improving both patient survival and their overall quality of life.
ORCID iD: https://orcid.org/0000-0001-7245-355X
PUBLICATION HIGHLIGHTS:
• 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, 14(19), 4648.