A compartment-adjustment framework reclassifies FOXC1 as a stromal-vascular readout in Luminal A breast cancer and recasts the basal-lineage "Centaur" signal as a tumour-population axis

BachkgroundCandidate tumour-cell biomarkers identified from bulk transcriptomes are frequently expressed in stromal or vascular compartments as well, so a bulk correlation between such a gene and a biological programme can reflect tumour-cell biology or co-variation with those compartments. FOXC1, a PAM50 basal-defining transcription factor with canonical vascular expression, has immune associations in Luminal A (Luminal A) breast cancer that have been read as tumour-cell-intrinsic. MethodsWe developed a compartment-adjustment framework--purity- and stroma-adjusted partial correlations benchmarked across candidate marker genes--and applied it across three Luminal A cohorts (TCGA, n = 571; METABRIC, n = 700; SCAN-B, n = 1,540; two sequencing platforms) and single-cell data (GSE176078; 100,064 cells). ResultsFOXC1s apparent adaptive-immune and tertiary-lymphoid-structure coupling is a vascular readout: it attenuates under adjustment for leukocyte-adhesion endothelial markers but persists under a structural-only endothelial composite, marking immune-recruiting vasculature. Single-cell analysis localises FOXC1 to the vessel wall--malignant cells contribute 1.8% of FOXC1 transcripts versus 90% from endothelial and perivascular cells. Basal cytokeratins (KRT5, KRT14, KRT17) and TP63, unlike FOXC1, retain a residual population-level basal-lineage signal; an apparent survival advantage is largely age-explained. ConclusionsBulk FOXC1 in Luminal A originates principally from stromal-vascular compartments. Compartment adjustment offers a candidate approach for interpreting bulk biomarkers in heterogeneous tissue.