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
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Bachkground
Candidate 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.
Methods
We 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).
Results
FOXC1 ’s 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.
Conclusions
Bulk FOXC1 in Luminal A originates principally from stromal–vascular compartments. Compartment adjustment offers a candidate approach for interpreting bulk biomarkers in heterogeneous tissue.
