Abstract 6575: Investigating the role of glucocorticoid-induced leucine zipper (GILZ) in triple-negative breast cancer

Abstract Breast cancer is one of the leading causes of death for American women, with 1 in 8 expected to develop the disease in their lifetime. Breast cancers that lack the expression of hormone receptors (estrogen/progesterone) and the HER2 receptor are known as triple negative breast cancer (TNBC). TNBC accounts for about 15-20% of all breast cancer cases in American women, and is commonly characterized by a complex tumor microenvironment that often exhibits increased inflammation and immune suppression. This makes TNBC resistant to many treatments, resulting in an overall lower five-year survival rate than other breast cancer subtypes.Evidence found in our lab demonstrates that the gene TSC22D3 is correlated with longer survival in patients with TNBC. TSC22D3 encodes the immunomodulatory protein Glucocorticoid-Induced Leucine Zipper (GILZ). GILZ expression is induced by glucocorticoid binding to hormone response elements in the nucleus and is thought to be one of the first transcripts synthesized after GR activation. GILZ is known to directly inhibit inflammation and cell proliferation by preventing downstream phosphorylation or activation events of enzymes such as mitogen-activated protein kinases (MAPKs), and proteins like rat sarcoma protein (Ras) and hypoxia inducible factor 1 alpha (HIF1a) to suppress inflammatory signaling.While the function and effects of the GILZ protein have been previously studied in many systems including the renal system, central nervous system and digestive system, its expression and effects have not been explicitly observed in breast cancer studies. Furthermore, the mechanism by which GILZ inhibits inflammation is variable with oxygen availability and the biological reason for this also remains unknown. The goal of this project is to 1) identify a potential chemical compound to modulate GILZ expression to better observe the activity in vitro and, 2) investigate key protein-protein interactions that influence GILZ action in variable oxygen availability states in TNBC cells. This work seeks to explore and clarify the specific immunomodulatory effects of GILZ in adaptable tumor microenvironments by investigating existing compounds that can reduce or overexpress GILZ protein levels and examining potential biased protein binding across different environments. All told, characterizing the activity and role of GILZ in varying conditions will potentially lead to the development of targeted therapeutic treatment for inflammation-driven diseases such as triple negative breast cancer. Citation Format: Devyn Aniya Hill, Jennifer B. Jacob. Investigating the role of glucocorticoid-induced leucine zipper (GILZ) in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6575.