Invasive lobular carcinoma is characterized by IL33-high differentiated endothelium and IL33 receptor-positive mast-cell enrichment

Invasive lobular carcinoma (ILC) differs from invasive ductal carcinoma (IDC) in growth pattern and clinical behavior, yet its vascular microenvironment remains poorly characterized. IL33 is expressed in differentiated endothelium and decreases with angiogenic activation, while its receptor IL1RL1/ST2 is prominently expressed by mast cells. We hypothesized that ILC preserves an IL33-high differentiated endothelial state with enrichment of IL1RL1/ST2-expressing mast cells. We analyzed TCGA-BRCA, METABRIC, and SCAN-B, focusing on luminal ILC versus luminal IDC, using gene-expression modules for endothelial, venular, sprouting, mast-cell, and proliferation states, with vascular comparisons adjusted for endothelial abundance. Single-cell RNA-seq, spatial transcriptomics, immune deconvolution, and outcome datasets provided orthogonal validation. Across bulk cohorts, ILC showed higher IL33, greater endothelial content, higher venular and mast-cell scores, and lower proliferation. After endothelial adjustment, IL33 remained higher and sprouting significantly lower in ILC across all three cohorts. In TCGA, differentiated vascular features followed a normal breast > ILC > IDC pattern, whereas mast-cell abundance was highest in ILC. IL1RL1 strongly correlated with mast-cell abundance, and adjustment for mast-cell content abolished the ILC-associated increase in IL1RL1; ST2 isoform composition was essentially unchanged. Single-cell analyses localized IL33 to differentiated venular endothelium and showed depletion in angiogenic/tip cells, while mast cells comprised a disproportionate fraction of IL1RL1-positive cells. Spatial transcriptomics showed mast-cell-containing regions preferentially localized to vessel-rich, venular environments without angiogenic enrichment. Higher endothelial-adjusted sprouting was associated with worse outcome. These findings define a distinctive vascular-immune microenvironment in ILC characterized by IL33-high differentiated endothelium, reduced angiogenic sprouting, and enrichment of IL1RL1-expressing mast cells.