Abstract 997: The cholesterol metabolite 27-hydroxycholesterol promotes breast cancer progression by affecting immune responses

Abstract

With upwards of 90% of mortalities associated with breast cancer being attributed to metastasis, there is an urgent need to better understand what drives this stage of disease. In this regard, it has been reported that an elevated concentration of circulating cholesterol is an independent risk factor for breast cancer recurrence. Supporting the relationship between cholesterol and breast cancer progression, the use of cholesterol lowering drugs (statins) has been demonstrated to improve recurrence-free survival. These clinical observations suggest that cholesterol influences the metastatic progression of breast cancer. Therefore, in this study we directly tested the impact of cholesterol on breast cancer metastasis, and interrogated the downstream mechanisms by which it may be doing so. In strong support of our hypothesis, increased metastasis was observed when mice were placed on a high cholesterol diet. These findings highlighted recent work by us and others demonstrating that the primary metabolite, 27-hydroxycholesterol (27HC), was able to modulate the activities of two hormone receptors: the estrogen and the liver X receptors. Thus, we pursued a series of experiments to determine whether 27HC was responsible for the metastatic actions of cholesterol. 27HC is synthesized from cholesterol by the enzyme CYP27A1. The genetic ablation of CYP27A1 completely attenuated the effects of a high cholesterol diet, implicating 27HC as a primary mediator of cholesterol. Treatment with exogenous 27HC robustly increased metastasis. Importantly, genetic or pharmacologic inhibition of CYP27A1 also reduced the basal metastatic burden, indicating that this enzyme may be a suitable target for the prevention and/or treatment of metastatic breast cancer. Intriguingly, we found that the pro-metastatic effects of 27HC also required the presence of myeloid cells, which was demonstrated by their ablation using clodronate-loaded liposomes. In the absence of myeloid cells, the ability of 27HC to promote metastasis was dramatically reduced. Whilst interrogating the distal metastatic site, we found that this oxysterol enriched Ly6G+/CD11b+ polymorphonuclear-neutrophils (PMNs) and γδ T cells. The induction of metastasis by 27HC was lost in models where either PMNs or γδ T cells were ablated. We further demonstrate that 27HC treatment results in a decrease in cytotoxic CD8+ T cells, suggesting that the net result of the 27HC enriched γδ T cells and PMNs is local immune suppression. Collectively, our results demonstrate that cholesterol increases metastasis via the actions of its metabolite 27HC, which exerts its effects through γδ T cells and PMNs to suppress acquired immunity. Since 27HC acts on the host environment to promote breast cancer progression, these results strongly support the immediate translational potential of targeting the 27HC pathway for the prevention and treatment of metastasis. Citation Format: Amy E. Baek, Sisi He, Hannah B. McDowell, Erik R. Nelson. The cholesterol metabolite 27-hydroxycholesterol promotes breast cancer progression by affecting immune responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 997.