Impact of 27-Hydroxycholesterol, a Macrophage-Produced Estrogen Receptor and Liver X Receptor Agonist, on Breast Cancer Pathophysiology

摘要

We and others have recently demonstrated that 27-hydroxycholesterol (27HC) can act as a partial agonist for the estrogen receptors (ERs)and liver X receptors (LXRs). Macrophages are considered a major source of 27HC and macrophage infiltration is associated with more aggressive breast tumors. The goal of this study was to determine the impact of 27HC on breast cancer pathophysiology and evaluate the relative contributions of the ERs and LXRs in this regard. In this reporting period we show that LXR activation does not affect the basal proliferation rate of either ER positive or ER negative cell lines. However, LXR activation does decrease estradiol-mediated proliferation. LXR ligands alter the expression of known ER target genes in a differential manner. Macrophages secrete factors which alter the expression of known ER target genes, and we have confirmed that the products of CYP27A1 action are important among the macrophage secreted factors. In order to truly assess the consequences of macrophage secreted 27HC on breast tumor pathophysiology, we have generated genetic mouse models that will either have altered 27HC synthesis or metabolism. Finally, we show that elevation of 27HC increases primary tumor growth, decreases the time to a second detectible tumor, and increases the overall tumor burden of our model mice. In conclusion, we have made substantial progress on this project and believe that we are on schedule to complete the project on time. It is anticipated that at the conclusion of this study we will have a clear understanding of the role of 27HC on breast tumor pathophysiology.