Abstract A14: A cholesterol metabolite acts on the host to increase breast cancer metastasis

Abstract

Abstract With a woman's lifetime risk of developing invasive breast cancer at one in eight, breast cancer remains the most common cancer and the second leading cause of cancer death in women. Despite the success of frontline endocrine therapies, relapse with resistant metastatic disease is common, and triple negative disease remains without a targeted therapy. Importantly, breast cancer associated mortality is most often due to the metastatic spread of the disease. Therefore, there continues to be a need for studies that may lead to the development of new chemopreventive strategies and/or lifestyle changes that reduce breast cancer metastasis. In this regard, both obesity and elevated cholesterol are risk factors for metastatic relapse, while patients receiving cholesterol-lowering drugs such as HMG-CoA reductase inhibitors (statins) display an increased relapse-free survival time. Therefore, clinical observations strongly implicate cholesterol in the metastatic progression of, although the underlying mechanisms remain unknown. Thus, we initiated a series of studies to evaluate the mechanisms by which cholesterol promotes breast cancer metastasis. Using murine models of mammary cancer, we find that elevated cholesterol does indeed increase metastasis. Further, statins attenuated the metastatic effects of a high fat diet, implicating cholesterol as a primary mediator of this pathology. Importantly, the pro-metastatic effects of cholesterol required the presence of CYP27A1, the enzyme responsible for its conversion to 27-hydroxycholesterol (27HC). We have recently shown that 27HC is an endogenous ligand for the both the estrogen receptors (ERs) and liver X receptors (LXRs). Interestingly, however, the metastatic effects of 27HC were also prevalent in ER-negative models. While LXR activation did have a modest effect on epithelial to mesenchymal transition (EMT), we find that the robust pro-metastatic effects of 27HC are mediated in a cancer cell-extrinsic manner. Specifically, we find that 27HC alters myeloid cell recruitment and function at distal metastatic sites, and thereby facilitates cancer cell colonization and growth by modulating the host environment. In summary, our data strongly suggest that by altering the host immune system, 27HC is the down-stream mediator of the effects of obesity and cholesterol on breast cancer metastasis. These results provide additional support for development of specific CYP27A1 inhibitors and immune-modulatory therapies for the prevention and treatment of breast cancer metastasis. This work was supported by an NIH-NCI grant to ERN (4R00CA172357-03). Citation Format: Amy Eun Joo Baek, Erik Russell Nelson. A cholesterol metabolite acts on the host to increase breast cancer metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A14.