Study on Heparanase Promoting Breast Cancer Cell Proliferation and Inhibiting NK Cell Cytolytic Activity Via the PD-1/PD-L1 Pathway.

Abstract

Objective: To explore the mechanism of action of heparanase (HPSE) in breast cancer (BC), particularly its impact on BC cell proliferation and natural killer (NK) cell cytolytic activity through the programmed cell death protein 1 (PD-1)/PD ligand 1 (PD-L1) pathway.

Methods: HPSE expression levels were analyzed in BC cells. MDA-MB-231 cells, a widely used triple-negative BC model, were treated and assessed using RT-qPCR and Western blotting for gene and protein expression. CCK-8, Transwell assays, and flow cytometry were used to evaluate cell proliferation, migration, invasion, and apoptosis. NK cells isolated from healthy donors were treated with HPSE and co-cultured with BC cells to assess cytolytic activity through interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) release measurements. A nude mouse xenograft model was established to examine the in vivo effects of HPSE on tumor growth and NK cell function.

Results: HPSE overexpression enhanced BC cell proliferation, migration, and invasion, while reducing apoptosis. It also upregulated PD-1 and PD-L1 expression, leading to impaired NK cell cytolytic activity and decreased secretion of TNF-α and IFN-γ. Inhibition of the PD-1/PD-L1 pathway partially reversed the pro-tumor effects of HPSE and restored NK cell cytolytic function. In vivo, HPSE overexpression promoted tumor growth and reduced NK cell activity within tumor tissues.

Conclusion: These findings reveal HPSE as a key regulator of BC immune evasion, likely via modulation of the PD-1/PD-L1 axis. Targeting HPSE, particularly in combination with PD-1/PD-L1 inhibitors, may offer a novel therapeutic strategy for BC treatment.