27-Hydroxycholesterol links cholesterol and breast cancer pathophysiology

The cholesterol metabolite and SERM, 27HC, is the signaling molecule that links cholesterol to breast cancer pathophysiology Hypercholesterolemia is a risk factor for breast cancer, and patients taking statins demonstrate lower breast cancer incidence and decreased breast cancer recurrence, data that highlights the potential importance of the recent finding that 27-Hydroxycholesterol (27HC), a primary metabolite of cholesterol, acts as a selective estrogen receptor modulator (SERM). The goal of this study was to evaluate the impact of 27HC on breast cancer pathophysiology. Elevation of 27HC in murine models increased tumor growth in an estrogen receptor dependent manner. Importantly, a high cholesterol diet decreased the time to tumor onset and increased tumor growth, and this response required presence of CYP27A1. Within human breast cancer samples, CYP27A1 expression increasesd with grade, in addition to being highly expressed in tumor associated macrophages. Finally 27HC increases metastasis to the lung. The findings herein strongly support a role for 27HC in breast cancer pathophysiology, providing support for the exploration of potential chemopreventative benefits of lower cholesterol diets, and pharmacological inhibitors of HMG-CoA reductase or CYP27A1. MCF-7 cells were treated as indicated in the presence of E2 or vehicle; RNA was isolated and used for preparation of label for 3' expression analysis.