Clinical Relevance and Drug Modulation of PPAR Signaling Pathway in Triple-Negative Breast Cancer: A Comprehensive...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Triple-negative breast cancer (TNBC) is a challenging subtype with limited treatment options.
• Peroxisome proliferator-activated receptors (PPARs) are key regulators of metabolism and cell fate, but their role in TNBC is not well understood.

Purpose of the Study:

• To comprehensively investigate the clinical relevance and drug modulation of the PPAR signaling pathway in TNBC.
• To explore the association between PPAR activity and TNBC characteristics, molecular pathways, and drug sensitivity.

Main Methods:

• Integrated analysis of The Cancer Genome Atlas (TCGA) data for TNBC patients and Genomics of Drug Sensitivity in Cancer (GDSC) data for TNBC cell lines.
• Utilized Connectivity Map (CMap) for drug perturbation information.
• Experimental validation using the histone deacetylase (HDAC) inhibitor chidamide.

Main Results:

• Higher PPAR signaling activity in TNBC was linked to older age, PCLO mutations, and oncogenic pathways (MAPK, Ras, PI3K-Akt).
• PPARs influenced fatty acid metabolism, AMPK signaling, ferroptosis, and promoted an antitumor immune microenvironment.
• PPAR activity was associated with chemoresistance in TNBC cell lines.
• Chidamide was shown to activate PPAR signaling in TNBC cells.

Conclusions:

• The PPAR signaling pathway exhibits pleiotropic effects in TNBC, influencing metabolism, immunity, and drug response.
• Findings provide new insights into TNBC heterogeneity and potential therapeutic targets involving PPAR modulation.