VDR-Mediated Inhibition of Glycolysis and Metastasis by Calcitriol in Triple-Negative Breast Cancer

Area of Science:

• Oncology
• Molecular Biology
• Metabolism

Background:

• Triple-negative breast cancer (TNBC) is aggressive with limited treatment options and high metastatic potential.
• The vitamin D receptor (VDR) and hypoxia-inducible factor-1α (HIF-1α) pathway are implicated in cancer progression.

Purpose of the Study:

• To investigate the anti-metastatic effects of calcitriol (active vitamin D) in TNBC.
• To explore the role of the VDR-HIF-1α axis in calcitriol's mechanism of action against TNBC.

Main Methods:

• Established *in vivo* TNBC xenograft models (4T1 cells) and *in vitro* models (MDA-MB-231, 4T1 cells overexpressing HIF-1α).
• Assessed calcitriol's effects on metastasis, tumor growth, cell viability, migration, invasion, and glycolytic activity.
• Utilized VDR knockdown to confirm the receptor's role.

Main Results:

• Calcitriol inhibited lung metastasis and downregulated glycolysis in TNBC xenografts without impacting primary tumor growth.
• In vitro, calcitriol reduced cell viability, migration, and invasion by suppressing HIF-1α expression and key glycolytic regulators.
• VDR knockdown abrogated calcitriol's inhibitory effects, confirming VDR mediation.

Conclusions:

• Calcitriol exhibits anti-metastatic properties in TNBC by modulating the VDR-HIF-1α axis.
• Calcitriol inhibits TNBC glycolysis and epithelial-mesenchymal transition, suggesting a dual therapeutic approach.
• Calcitriol shows potential as a therapeutic agent for TNBC, targeting both metabolic reprogramming and invasive capabilities.