Thrombospondin‐4 mediates hyperglycemia‐ and TGF‐beta‐induced inflammation in breast cancer

Abstract Inflammation drives the growth of tumors and is an important predictor of cancer aggressiveness. CD68, a marker of tumor‐associated macrophages (TAM), is routinely used to aid in prognosis and treatment choices for breast cancer patients. We report that thrombospondin‐4 (TSP‐4) mediates breast cancer inflammation and growth in mouse models in response to hyperglycemia and TGF‐beta by increasing TAM infiltration and production of inflammatory signals in tumors. Analysis of breast cancers and noncancerous tissue specimens from hyperglycemic patients revealed that levels of TSP‐4 and of macrophage marker CD68 are upregulated in diabetic tissues. TSP‐4 was colocalized with macrophages in cancer tissues. Bone‐marrow‐derived macrophages (BMDM) responded to high glucose and TGF‐beta by upregulating TSP‐4 production and expression, as well as the expression of inflammatory markers. We report a novel function for TSP‐4 in breast cancer: regulation of TAM infiltration and inflammation. The results of our study provide new insights into regulation of cancer growth by hyperglycemia and TGF‐beta and suggest TSP‐4 as a potential therapeutic target.