Prognostic Value of IGFBP6 in Breast Cancer: Focus on Glucometabolic

IGFBP6, as a member of the IGF binding proteins (IGFBPs) family, is a specific inhibitor of insulin-like growth factor II (IGF-II) and can inhibit the growth of malignant tumors overexpressing IGF-II. Type 2 diabetes (T2D) is a basic disorder of glucose metabolism which is regulated by IGF-related pathways. IGFBP6 expression is downregulated in serum and tumor tissue of colorectal cancer patients with T2D. We analyzed the TCGA database by bioinformatics to explore the possible mechanism of IGFBP6 in breast cancer (BC) metabolism and prognosis, and collected clinical samples of BC patients with T2D and without T2D to compare and verify the prognostic effect of IGFBP6. The results showed that IGFBP6 was up-regulated in estrogen receptor (ER) positive BC. The results of validation cohort confirmed that IGFBP6 could be used as an independent prognosis predictor of BC. The expression of IGFBP6 was decreased in BC tissue, and the BC tissue with T2D had lower IGFBP6 expression level compared with the non-T2D BC tissue. IGFBP6 is mainly involved in the PI3K − Akt and TGF-β signal pathways and tumor microenvironment regulation. In terms of metabolism, the expression of IGFBP6 was negatively correlated with most glucose metabolism-related genes. IGFBP6 was mainly correlated with the mutation of TP53, PIK3CA, CDH1, MAP3K1. In addition, up-regulation of IGFBP6 in BC increased the drug sensitivity of docetaxel, paclitaxel and gemcitabine. Overall, high expression of IGFBP6 was associated with good prognosis of BC, especially in non-T2D BC patients. It was not only involved in tumor microenvironment maintenance of BC, but also inhibited the energy metabolism of cancer cells through glucose metabolism-related pathways. These findings may provide a new perspective on IGFBP6 as a potential prognosis marker for BC.