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Zoledronic acid blocks the interaction between breast cancer cells and regulatory T-cells
Hsien Liu1, Shih-Han Wang2, Shin-Cheh Chen3
1Department of Surgery, Chi Mei Medical Center, Liouying, Tainan, Taiwan.
Background:
Zoledronic acid (ZA), a nitrogen-containing bisphosphonate, inhibits osteoclastogenesis. Emerging evidence suggests that ZA has anti-tumor and anti-metastatic properties for breast cancer cells. In a mouse model of ZA-related osteonecrosis of the jaw, ZA administration was found to suppress regulatory T-cells (Tregs) function. Our previous reports also demonstrated ZA acted as an immune modulator to block Tregs. Manipulation of Tregs represents a new strategy for cancer treatment. However, the relationship among ZA, Tregs, and cancer cells remains unclear. In this study, we investigated the effects of ZA on the interaction of breast cancer cells and Tregs.
Methods:
The anti-tumor effect of ZA on triple negative breast cancer cell lines were validated by XTT, wound healing and apoptosis analysis. A flow cytometry-based assay was used to analyze the immunosuppressive effect of Tregs treated with media conditioned by breast cancer cells, and a transwell assay was used to evaluate the chemotactic migration of Tregs. Differential gene expression profile on MDA-MB-231 treated with ZA (25 μM) was analyzed by. microarrays to describe the molecular basis of actions of ZA for possible direct anti-tumor effects. Enzyme-linked immunosorbent assays and quantitative real-time PCR were used to investigate the effect of ZA on the expression of cytokines/factors by breast cancer cells.
Results:
ZA was found to inhibit the proliferation and migration of breast cancer cells. Media conditioned by the MDA-MB-231 cells promoted the expansion, chemotactic migration, and immunosuppressive activity of Tregs, and these effects were attenuated in a dose-dependent manner by ZA treatment, and the attenuation was due to reduced expression of selected breast cancer cell factors (CCL2, CCL5, and IDO).
Conclusions:
ZA can significantly affect the interaction between breast cancer cells and Tregs. Our findings indicate that ZA is a potential therapeutic agent that can be used to reduce cancer aggressiveness by abolishing the supportive role of Tregs.
Insights
Zoledronic acid (ZA) inhibits breast cancer cell growth and migration. ZA also reduces the supportive role of regulatory T-cells (Tregs) in breast cancer, suggesting a new therapeutic strategy.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Zoledronic acid (ZA), a bisphosphonate, is known to inhibit osteoclastogenesis and shows potential anti-tumor properties.
- Emerging evidence suggests ZA modulates regulatory T-cells (Tregs), which play a role in cancer progression.
- The precise interaction between ZA, Tregs, and breast cancer cells requires further investigation.
Purpose of the Study:
- To investigate the effects of Zoledronic acid (ZA) on the interaction between breast cancer cells and regulatory T-cells (Tregs).
- To explore ZA's potential as a therapeutic agent by understanding its impact on cancer cell aggressiveness and immune modulation.
Main Methods:
- Validated anti-tumor effects of ZA on triple-negative breast cancer cell lines using XTT, wound healing, and apoptosis assays.
- Analyzed Treg immunosuppressive effects and chemotactic migration using flow cytometry and transwell assays.
- Investigated molecular mechanisms via gene expression profiling and analysis of cytokine/factor expression by breast cancer cells.
Main Results:
- Zoledronic acid (ZA) inhibited breast cancer cell proliferation and migration.
- Media from MDA-MB-231 cells enhanced Treg expansion, migration, and immunosuppression.
- ZA dose-dependently attenuated these Treg-supportive effects by reducing cancer cell expression of CCL2, CCL5, and IDO.
Conclusions:
- Zoledronic acid (ZA) significantly modulates the interaction between breast cancer cells and Tregs.
- ZA demonstrates potential as a therapeutic agent to reduce cancer aggressiveness by diminishing the supportive functions of Tregs.
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