Abstract 307: Triple-negative breast cancer growth and metastasis suppression by CCN5 is mediated by Merlin/NF2 and Orai-1 molecular signatures.

Abstract Breast cancer (BC) is the second leading cause of cancer-related death among women, both in the United States and globally. This disease affects approximately one in eight women (around 12%), impacting nearly every family worldwide. The statistics are similarly relevant for female U.S. veterans. Current therapies for BC are thought to improve patient survival; however, one-third of patients with aggressive triple-negative breast cancer (TNBC) may experience more frequent relapses compared to those with hormone receptor-positive subtypes, and may eventually develop distant metastatic disease. Currently, there are no targeted therapies available for invasive and metastatic breast cancer, highlighting a critical need for improved treatment options. TNBC is a heterogeneous mix of cells, with significant variability both between and within tumors, which often makes therapeutic regimens less effective. A novel approach, diverging from existing treatment strategies, could positively influence both clinical study designs and future practices in BC, potentially increasing the number of TNBC survivors. Our previous studies examined CCN5 expression in a large cohort of primary BC samples and cell lines, finding that CCN5 expression is inversely correlated with disease in most samples. In this study, we demonstrated that CCN5 inhibits tumor growth and metastatic spread in genetically engineered mouse models (GEMMs) and human TNBC xenograft models, without causing any side effects. CCN5 may facilitate these critical processes by regulating the expression and activity of Merlin (a tumor suppressor gene) and Orai1 (a gene involved in metastasis) in TNBC cells. In addition, CCN5 suppresses the JunB/AP-1 transcription factor and VEGF-A, while protecting against ZO-1 loss (a downstream target of VEGF-A and a protein that acts as a barrier to metastasis), mirroring the blockade of permeability in endothelial cell (EC) monolayers. These collective findings suggest that CCN5 prevents or delays the growth, invasion, and metastasis of TNBC cells by regulating multiple gene signatures. Therefore, CCN5 treatment or restoration may represent a promising novel therapeutic intervention for breast cancer. (This work is supported by the VA Merit grants) Citation Format: Inamul Haque, Gargi Maity, Jamie L. Porter, Snigdha Banerjee, Sushanta K. Banerjee. Triple-negative breast cancer growth and metastasis suppression by CCN5 is mediated by Merlin/NF2 and Orai-1 molecular signatures [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 307.