Abstract A82: The cholesterol metabolite, 27-hydroxycholesterol, promotes breast cancer metastasis

Abstract

Abstract Breast cancer remains the most common cancer in women and is the second leading cause of cancer death in women. It is important to note that the majority of patients eventually succumb to the metastatic spread of their disease, not to the primary tumor itself. The magnitude of this problem provides strong rationale for studies that may lead to the development of new chemopreventative strategies and/or lifestyle changes that reduce breast cancer metastasis. It is of significance, therefore, that patients taking inhibitors of 2-hydroxy-3-methylglutaryl coenzyme A (statins) experience a significantly increased relapse free survival time. Therefore, our recent finding that 27-Hydroxycholesterol (27HC), a primary metabolite of cholesterol, exerts partial agonist activity on both the estrogen receptors (ERs) and liver X receptors (LXRs), suggests a potential mechanistic link between hypercholesterolemia and breast cancer pathology. We demonstrate that 27HC (1) increases in vivo tumor growth and lung metastases, (2) promotes an epithelial to mesenchymal like transition, and (3) in a myeloid cell dependent manner, alters the metastatic microenvironment to promote cancer cell colonization. Our ongoing work is aimed at identifying the specific mechanisms by which 27HC induces these changes and thereby increases metastasis. In summary, our data thus far strongly indicate a role for 27HC in breast cancer pathophysiology and metastasis. These results provide additional support for the exploration of potential chemopreventative benefits of lower cholesterol diets, pharmacological inhibitors of HMG-CoA reductase or the enzyme responsible for the synthesis of 27HC (CYP27A1), and macrophage ablative strategies. This work was supported by an NIH-NCI grant to ERN (4R00CA172357-03). Citation Format: Erik Russell Nelson, Suzanne E. Wardell, Donald P. McDonnell. The cholesterol metabolite, 27-hydroxycholesterol, promotes breast cancer metastasis. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A82.