Integrative analysis of mRNA and miRNA expression profiles and somatic variants in oxysterol signaling in early-stage luminal breast cancer.

Oxysterols, oxidized derivatives of cholesterol, act in breast cancer (BC) as selective estrogen-receptor modulators and affect cholesterol homeostasis, drug transport, nuclear and cell receptors, and other signaling proteins. Using data from three highly overlapping sets of patients (N=162 in total) with early-stage estrogen-receptor-positive luminal BC-high-coverage targeted DNA sequencing (113 genes), mRNA sequencing, and full micro-RNA (miRNA) transcriptome microarrays-we describe complex oxysterol-related interaction (correlation) networks, with validation in public datasets (n=538) and 11 databases. The ESR1-CH25H-INSIG1-ABCA9 axis was the most prominent, interconnected through miR-125b-5p, miR-99a-5p, miR-100-5p, miR-143-3p, miR-199b-5p, miR-376a-3p and miR-376c-3p. Mutations in SC5D, CYP46A1, and its functionally linked gene set were associated with multiple differentially expressed oxysterol-related genes. STARD5 was upregulated in patients with positive lymph-node status. High expression of hsa-miR-19b-3p was weakly associated with poor survival. This is the first study of oxysterol-related genes in BC that combines DNA, mRNA and miRNA multi-omics with detailed clinical data. Future studies should provide links between intra-tumoral oxysterol signaling depicted here, circulating oxysterols levels, and therapy outcomes, enabling eventual clinical exploitation of present findings.