HYPERGLYCEMIA-INDUCED MIR-467 DRIVES TUMOR INFLAMMATION AND GROWTH IN BREAST CANCER

Abstract

ABSTRACTTumor microenvironment contains the parenchyma, blood vessels, and infiltrating immune cells, including tumor-associated macrophages (TAMs). TAMs affect the developing tumor and drive cancer inflammation.Hyperglycemic patients have a higher risk of developing breast cancer (BC). We have identified a novel miRNA-dependent pathway activated by hyperglycemia that promotes BC angiogenesis and inflammation supporting BC growth. miR-467 is upregulated in endothelial cells (EC), macrophages, BC cells, and in BC tumors. A target of miR-467, thrombospondin-1 (TSP-1), inhibits angiogenesis and promotes resolution of inflammation. Systemic injections of a miR-467 antagonist in mouse models of hyperglycemia resulted in decreased BC growth (P<.001). Tumors from hyperglycemic mice had a 2-fold increase in macrophage accumulation compared to normoglycemic controls (P<.001), and TAM infiltration was prevented by the miR-467 antagonist (P<.001). BC specimens from hyperglycemic patients had increased miR-467 levels, increased angiogenesis, decreased levels of TSP-1, and increased TAM infiltration in malignant breast tissue in hyperglycemic vs normoglycemic patients (2.17-fold, P=.002) and even in normal breast tissue from hyperglycemic patients (2.18-fold inc., P=.04). In malignant BC tissue, miR-467 levels were upregulated 258-fold in hyperglycemic patients compared to normoglycemic patients (P<.001) and increased 56-fold in adjacent normal tissue (P=.008).Our results suggest that miR-467 accelerates tumor growth by inducing angiogenesis and promoting the recruitment of TAMs to drive hyperglycemia-induced cancer inflammation.