Integrated transcriptomic, protein, and MicroRNA profiling reveals a conserved pyroptosis-related molecular signature...

Pyroptosis, an inflammatory form of programmed cell death, has been implicated in tumor progression, yet its molecular contribution across breast cancer subtypes remains poorly defined.

To characterize pyroptosis-related alterations, we analyzed tumor and matched control tissues from five molecular subtypes of breast cancer using genome-wide messenger RNA and microRNA microarrays, quantitative polymerase chain reaction, enzyme-linked immunosorbent assays, and protein-protein interaction analysis. We identified predicted microRNA-messenger RNA regulatory relationships and constructed a pyroptosis index and inflammasome activation score. To contextualize these findings, temporal expression changes were evaluated in a cryoablation model of benign fibroadenoma.

Nine genes associated with inflammatory and apoptotic signaling-CXCL8, BCL2, BAX, CASP1, CASP9, TP53, CDKN1A, CDKN1B, and MMP9-consistently distinguished cancerous from control tissue across all subtypes at both messenger RNA and protein levels. Aggressive subtypes, particularly human epidermal growth factor receptor 2-enriched and triple-negative tumors, exhibited pronounced activation of inflammasome-related pathways, elevated pyroptosis index and inflammasome activation score values, and coordinated suppression of cell-cycle inhibitors. Predicted microRNA regulators, including microRNA 140-3p, microRNA 124-3p, microRNA 300, microRNA 30a-3p, microRNA 30d-3p, and microRNA 608, showed patterns consistent with loss of post-transcriptional restraint in high-grade tumors. In fibroadenoma, pyroptosis-associated expression changes were rapid and transient, whereas malignant tissue displayed a consistent, subtype-dependent elevation of pyroptosis-related markers at the time of resection.

This integrative analysis identifies a conserved pyroptosis-related molecular signature that deepens understanding of inflammatory programmed cell death in breast cancer and highlights interconnected pathways with diagnostic, prognostic, and therapeutic relevance.