Project description: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 overlapping data from patients with early-stage estrogen receptor-positive BC—high-coverage targeted DNA sequencing (99 patients, 113 genes), mRNA sequencing (67 patients), and full miRNome by microarrays (123 patients)—we describe complex mRNA-miRNA and miRNA-miRNA interaction (correlation) networks, with validation in two carefully curated public datasets (n=538 in total) and 11 databases. The ESR1-CH25H-INSIG1-ABCA9 axis was the most prominent, being interconnected through hsa-miR-125b-5p, but also hsa-miR-99a-5p, hsa-miR-100-5p, hsa miR 143 3p, hsa-199b-5p, hsa-miR-376a-3p, and hsa-miR-376c-3p. Mutations in SC5D, CYP46A1, and its functionally linked gene set were associated with multiple differentially expressed genes. STARD5 was upregulated in patients with positive lymph node status. High expression of miR-19b-3p was weakly associated with poor survival in multiple datasets. This is the first detailed dedicated study of interactions between DNA variation and mRNA expression of oxysterol-related genes, the miRNA transcriptome, and clinical factors in BC.
