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

Triple-negative breast cancer (TNBC) is highly heterogeneous and poses a significant medical challenge due to limited treatment options and poor outcomes. Peroxisome proliferator-activated receptors (PPARs) play a crucial role in regulating metabolism and cell fate. While the association between PPAR signal and human cancers has been a topic of concern, its specific relationship with TNBC remains unclear. Integrated analysis of large published datasets from clinical cohorts and cell lines through databases has proven to be a powerful and essential approach for understanding cancer and uncovering new molecular targets. Here, we conducted a comprehensive study investigating the clinical relevance and drug modulation of the PPAR signaling pathway in TNBC, using data from The Cancer Genome Atlas (TCGA) for TNBC patients and Genomics of Drug Sensitivity in Cancer (GDSC) for TNBC cell lines, along with drug perturbation information from Connectivity Map (CMap). In the TCGA-TNBC cohort, higher PPAR signaling activity was not associated with clinical stage, prognosis, tumor mutational burden, microsatellite instability, homologous recombination deficiency, stemness, or proliferation status. However, it was linked to older age; an elevated rate of piccolo presynaptic cytomatrix protein (PCLO) mutations; and oncogenic signal transduction involving MAPK, Ras, and PI3K-Akt pathways. Additionally, it influenced biological pathways including fatty acid metabolism, AMPK signaling, and ferroptosis. Strikingly, higher PPAR activity appeared to promote the formation of an antitumor immune and microbial microenvironment. In the GDSC-TNBC cells, nevertheless, it seemed to incur chemoresistance. Furthermore, we identified a batch of potential compounds that can regulate the PPAR signaling pathway. Lastly, our experimental validation demonstrated the ability of the histone deacetylase (HDAC) inhibitor chidamide to activate the PPAR signal in TNBC cells. In conclusion, the PPAR signaling pathway likely has pleiotropic biological effects in TNBC. These preliminary but interesting findings enhance our understanding of the role played by PPAR signal and provide new insights into the heterogeneity driven by it in TNBC.