Abstract 3866: A new approach to suppress triple-negative breast cancer metastasis by blocking apurinic/apyrimidinic endonuclease 1 interaction with G-quadruplex

Abstract Triple-negative breast cancer (TNBC) has a relatively high metastasis rate as compared to other breast cancer subtypes. Metastasis and tumor recurrence remain major challenges for TNBC patients, resulting in poor prognosis. Therefore, it is imperative to identify and elucidate the molecular mechanisms that drive metastasis to allow the development of new therapeutic agents to inhibit TNBC metastasis and improve patients’ outcomes. Herein, we uncovered a new mechanistic connection between a multifunctional DNA repair protein APE1 and G-quadruplex (G4), a secondary DNA structure present in many metastasis-related signature genes promoters in TNBC. We found that APE1 is highly enriched at the G4 regions on the promoters of metastasis related genes and APE1 knockout or knockdown impairs the tumorigenic and pro-metastatic traits of TNBC cell lines in vitro. Intriguingly, we found that G4 is required for APE1’s enrichment at these promoters and APE1 promotes transcription factors (TFs) binding to these promoters, thereby promoting the expression of these metastasis-related genes. Deletion of APE1 impeded TFs’ binding to promoters and downregulated expression of these genes. In addition, we found that G4 deletion in some target gene promoters exerted similar inhibitory effects as APE1 knockout on cell migration, cell invasion and tumor sphere formation. We discovered that a small molecule which disrupts APE1: G4 interaction significantly disrupted APE1’s enrichment to G4 on promoters, thereby blocking TFs binding, gene expression, cell migration, invasion and tumor sphere formation in vitro. We generated orthotopic TNBC metastasis mouse model using an aggressive TNBC cell line, MDA-MB-231 and found that disrupting G4-APE1 axis either by APE1 knockout or G4 deletion or small molecules significantly inhibited the primary tumor growth and impeded TNBC distant metastasis to lungs. Overall, our study uncovered a novel functional axis of G4-APE1 in regulating TNBC growth and metastasis and identified that this regulatory axis has the potential to serve as a new therapeutic target to prevent metastasis in TNBC patients. Citation Format: Yingling Chen, Suravi Pramanik, Mason Tarpley, Achyuth Kalluchi, Sutapa Ray, Bhopal Mohapatra, Kyle Hewitt, Jordan Rowley, Vimla Band, Kishor K. Bhakat. A new approach to suppress triple-negative breast cancer metastasis by blocking apurinic/apyrimidinic endonuclease 1 interaction with G-quadruplex [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 3866.