Empagliflozin Modulates Angiogenesis and Migration Through the NF-κB1 Axis in Breast Cancer Cells

Abstract Background/Aims: Triple-negative breast cancer (TNBC) and hormone receptor-positive breast cancer remain challenging to treat due to their aggressive behavior and resistance to conventional therapies. Empagliflozin (EMPA), a sodium-glucose co-transporter 2 (SGLT2) inhibitor, has recently attracted attention for its potential anticancer properties. This study aimed to evaluate the effects of EMPA on cell viability, migration, and gene expression in breast cancer cell lines, focusing on its role in modulating angiogenesis and epithelial-to-mesenchymal transition (EMT) pathways. Methods: The effects of EMPA were assessed in MDA-MB-231 (TNBC) and MCF-7 (Luminal A) breast cancer cell lines using WST-1 cytotoxicity assays, scratch wound migration assays, and quantitative reverse transcription PCR (qRT-PCR). Gene expression analyses were conducted for NF-κB, N-cadherin, VEGFA, and FGF1 to investigate EMPA’s impact on inflammation, angiogenesis, and EMT. Results: EMPA exhibited dose-dependent cytotoxicity, with MCF-7 cells showing greater sensitivity (IC₅₀: 521 µM) compared to MDA-MB-231 cells (IC₅₀: 1080 µM). EMPA significantly inhibited cell migration in both cell lines. In MDA-MB-231 cells, qRT-PCR revealed downregulation of NF-κB, VEGFA, and FGF1, indicating anti-inflammatory and anti-angiogenic activity. In contrast, MCF-7 cells showed NF-κB upregulation along with VEGFA and FGF1 downregulation, suggesting a subtype-specific molecular response. Conclusions: EMPA suppresses breast cancer cell proliferation, migration, and angiogenic signaling, potentially through NF-κB modulation. Its distinct effects on different breast cancer subtypes suggest a context-dependent therapeutic potential. These findings support further investigation into EMPA as a repurposed agent for targeted breast cancer therapy, particularly in aggressive forms such as TNBC.