Hyperglycemia-Induced miR-467 Drives Tumor Inflammation and Growth in Breast Cancer

SIMPLE SUMMARY: The incidence of breast cancer is higher in diabetic patients. Cancers of diabetic patients are more aggressive and grow and spread faster than in patients without diabetes. We discovered a novel pathway that is regulated by high blood glucose and promotes breast cancer growth. We have previously studied the details of this pathway and found that it increases the growth of new blood vessels that feed the growing tumor. Our new results presented here suggest that, in addition to the effect on the growth of the cancer blood vessels, the same pathway regulates the inflammation in the tumor. Furthermore, we found that the regulator of this pathway, a small RNA molecule induced by high blood glucose, can be found in blood of animals with breast cancer tumor and thus, can be used as a marker of a tumor. Currently, there are no affordable methods to monitor the recurrence and metastases in breast cancer patients after the removal of the primary tumor. Monitoring miR-467 levels in blood may prove to be a cheap test that can be frequently performed. ABSTRACT: The tumor microenvironment contains the parenchyma, blood vessels, and infiltrating immune cells, including tumor-associated macrophages (TAMs). TAMs affect the developing tumor and drive cancer inflammation. We used mouse models of hyperglycemia and cancer and specimens from hyperglycemic breast cancer (BC) patients to demonstrate that miR-467 mediates the effects of high blood glucose on cancer inflammation and growth. Hyperglycemic patients have a higher risk of developing breast cancer. 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 < 0.001). Tumors from hyperglycemic mice had a two-fold increase in macrophage accumulation compared to normoglycemic controls (p < 0.001), and TAM infiltration was prevented by the miR-467 antagonist (p < 0.001). 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 = 0.002) and even in normal breast tissue from hyperglycemic patients (2.18-fold increase, p = 0.04). In malignant BC tissue, miR-467 levels were upregulated 258-fold in hyperglycemic patients compared to normoglycemic patients (p < 0.001) and increased 56-fold in adjacent normal tissue (p = 0.008). Our results suggest that miR-467 accelerates tumor growth by inducing angiogenesis and promoting the recruitment of TAMs to drive hyperglycemia-induced cancer inflammation.