Abstract
Obesity and elevated circulating cholesterol are risk factors for breast cancer recurrence, while the use of statins, cholesterol biosynthesis inhibitors widely used for treating hypercholesterolemia, is associated with improved disease-free survival. Here, we show that cholesterol mediates the metastatic effects of a high-fat diet via its oxysterol metabolite, 27-hydroxycholesterol. Ablation or inhibition of CYP27A1, the enzyme responsible for the rate-limiting step in 27-hydroxycholesterol biosynthesis, significantly reduces metastasis in relevant animal models of cancer. The robust effects of 27-hydroxycholesterol on metastasis requires myeloid immune cell function, and it was found that this oxysterol increases the number of polymorphonuclear-neutrophils and γδ-T cells at distal metastatic sites. The pro-metastatic actions of 27-hydroxycholesterol requires both polymorphonuclear-neutrophils and γδ-T cells, and 27-hydroxycholesterol treatment results in a decreased number of cytotoxic CD8+T lymphocytes. Therefore, through its actions on γδ-T cells and polymorphonuclear-neutrophils, 27-hydroxycholesterol functions as a biochemical mediator of the metastatic effects of hypercholesterolemia.
Highlights
Obesity and elevated circulating cholesterol are risk factors for breast cancer recurrence, while the use of statins, cholesterol biosynthesis inhibitors widely used for treating hypercholesterolemia, is associated with improved disease-free survival
We have shown that a high-cholesterol diet can increase the growth of ER-positive tumors in the murine MMTV-PyMT model, and that statin treatment could attenuate the effects of a high-fat diet on E0771 tumor growth[16]
Quantitative RT-PCR for PyMT transcript within the lung is presented in the graph and used to quantify metastasis since its expression should be restricted to mammary epithelial cells. f Chronic treatment with a small molecule inhibitor of CYP27A1, GW273297X (GW297X) decreases colonization of lung tissue from Met[1] i.v. grafts (N = 4 each). g Lung colonization from E0771 i.v. grafts in APOE3 mice is increased by a high-fat diet (HFD), but attenuated in mice chronically treated with GW297X (CD placebo N = 5, GW297X N = 3, HFD placebo N = 7, GW297X N = 6)
Summary
Obesity and elevated circulating cholesterol are risk factors for breast cancer recurrence, while the use of statins, cholesterol biosynthesis inhibitors widely used for treating hypercholesterolemia, is associated with improved disease-free survival. We report that an isocaloric diet high in cholesterol (HCD) alone was sufficient to increase metastasis in several pre-clinical models of mammary cancer, firmly establishing a causative effect of cholesterol on metastasis This activity could be attributed to effects of the cholesterol metabolite 27HC on myeloid cell function and was associated with increased numbers of polymorphonuclear neutrophils (PMNs) and γδ T cells, and decreased cytotoxic CD8+ T cells within tumors and metastatic lesions. These studies highlight the potential clinical utility of interfering with the production and/or activity of cholesterol and 27HC in patients with breast cancer and possibly other solid tumors
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