Abstract 6917: Developing a novel therapeutic approach to target EGR1 in aggressive breast cancer

Abstract Introduction: Aggressive breast cancer, e.g., Triple-negative breast cancer (TNBC) and inflammatory breast cancer (IBC), needs novel targeted therapies. The epidermal growth factor receptor (EGFR) is a central signaling molecule that promotes tumor growth and metastasis and creates an immunosuppressive tumor microenvironment (TME) in aggressive breast cancers. Our research has demonstrated that early growth response 1 (EGR1), which EGFR signaling pathway regulates its expression, is a central mediator to an immunosuppressive TME by regulating the expression of immunosuppressive chemokines, indicating EGR1 is a potential therapeutic target for patients with aggressive breast cancer. However, no inhibitors or therapeutic antibodies currently target EGR1, emphasizing the critical need for novel strategies to inhibit its activity. Because EGR1 gene expression is regulated by the cAMP response element-binding protein (CREB), we hypothesize that suppressing EGR1 expression by inhibiting CREB can downregulate immunosuppressive chemokines and lead to reduced tumor growth in aggressive breast cancer. In this study, we evaluated the effect of the novel CREB inhibitor on IBC and TNBC cell growth and the expression of immunosuppressive chemokines by modulating EGR1 expression. Methods: We evaluated the effects of the CREB inhibitor on EGR1 gene and protein expression in human IBC and TNBC cells (SUM149, HS578T, HCC1806, and HCC1937) and murine TNBC cells (E0771 and PyMT-N) in vitro using real-time PCR and Western blot analyses. Cell sensitivity to CREB inhibitor was assessed using the CellTiter-Blue assay. The expression of EGR1-regulated chemokines (CCL2, CCL20, CXCL5, and CXCL8) after CREB inhibitor treatment was examined using real-time PCR. Results: CREB inhibitor suppressed EGR1 gene expression in all tested cell lines and reduced EGR1 protein expression in SUM149, HS578T, E0771, and PyMT-N cells. The half-maximal inhibitory concentration (IC50) of TNBC cells to CREB inhibitor was 1.067 µM (HCC1806), 2.342 µM (HCC1937), 3.291 µM (E0771), and 1.622 µM (PyMT-N). Compared to DMSO control, CREB inhibitor treatment reduced the gene expression of CCL2, CCL20, and CXCL8 in human TNBC cells and that of CCL2, CCL20, and CXCL5 in murine TNBC cells. Conclusions: The CREB inhibitor suppressed the expression of the EGR1 gene and protein and decreased the expression of EGR1-regulated immunosuppressive chemokines, suggesting that a CREB inhibitor can effectively modulate EGR1 expression and function. We will further investigate the impact of targeting EGR1 with a CREB inhibitor on IBC and TNBC tumor growth and TME modulation in vivo. Citation Format: Suguru Ogata, Sophia McAneny-Droz, Manuel Van Gijsel-Bonnello, Verena Martinez-Rodriguez, Mark Miller, Bingbing Li, Naoto T. Ueno, Xiangshu Xiao, Xiaoping Wang. Developing a novel therapeutic approach to target EGR1 in aggressive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6917.