Identification of a tumor-promoter cholesterol metabolite in human breast cancers acting through the glucocorticoid receptor

Significance Cholesterol and its transformation into cholesterol-5,6-epoxides (5,6-EC) was long suspected as contributing to breast cancer (BC) pathogenesis, before it was found that 5,6-EC metabolism controls BC development and is deregulated in breast cancers. Herein, we studied in tumor cells and human samples how 5,6-EC metabolism deregulation promotes tumor progression. We have discovered a pathway in BCs producing an oncometabolite derived from 5,6-EC, through the action of the cortisol-inactivating enzyme, and identified the glucocorticoid receptor (GR) as the target mediating its proliferative effects. Inhibition of its production or GR significantly blocked its action on BC progression. Thus, targeting this oncometabolism and GR represents a new opportunity for therapeutic intervention in BCs and potentially other cancers presenting such deregulations.