PHGDH activity in Triple-Negative Breast Cancer studies--A glimmer of hope in the midst of difficult treatment process

Background: Triple-Negative Breast Cancer (TNBC), which lacks estrogen receptor, progesterone receptor and HER2 expression, has limited effective therapeutic options and unfavorable prognosis. Nicotinamide (NAM), a form of vitamin B3, has shown anti-tumor effects in TNBC, but the underlying regulatory mechanisms remains unclear. Methods: Transcriptomic and proteomic data from TNBC cell lines (BT20, MDA-MB-231, and MDA-MB-468) were analyzed using the ARACNe and VIPER/metaVIPER algorithms to infer regulatory activity and construct gene networks. Differentially expressed genes (DEGs) and proteins (DEPs) were integrated with regulator activity to identify key molecular drivers. Clinical outcomes were assessed using bc-GenExMiner and Kaplan-Meier Plotter, correlation and enrichment analyses were employed ICGC datasets and KEGG pathway mapping. Results: NAM treatment induced distinct but overlapping regulatory activity profiles among TNBC cell lines, with PHGDH, TSPAN1, TACSTD2, and OSBPL6 emerging as shared regulators. Among these, PHGDH, a key enzyme in the serine biosynthesis pathway, showed consistent downregulation across datasets and was associated with poor overall survival (p < 0.001). Correlation analysis across three ICGC cohorts identified 384 genes significantly associated with PHGDH, enriched in Glycine, serine and threonine metabolic pathways. Network analysis revealed potential interactions between PHGDH, ERBB3 and other regulatory proteins, suggesting crosstalk between metabolic and signaling pathways. Conclusions: This multi-omics integration highlights PHGDH as a central metabolic regulator linking transcriptional and translational responses to NAM treatment in TNBC. These findings support PHGDH as a potential biomarker and therapeutic target, emphasizing the role of metabolic regulation in TNBC progression and treatment response.