Figure legends:
Figure 1: A) Detailed chemical structure of: cholesterol, 27-hysdroxycholesterol (27-HC), 5,6α-epoxycholesterol (5,6α-EC), 5,6β-epoxycholesterol (5,6β-EC), 5,6α-epoxy-cholesterol-3β-sulfate (5,6-ECS), DDA: dendrogenin A, Cholestane-3β,5α,6β-triol (CT), 6-oxo-cholestan-3β,5α-diol (oncosterone). B) 5,6α-EC can react with histamine to give dendrogenin A in the presence of a chemical catalyst or an enzyme.C) 5,6-EC is hydrated by the cholesterol-5,6-epoxide hydrolase (ChEH) to give CT. CT is transformed into OCDO by the 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) to give oncosterone. The reverse reaction is catalysed by the 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) and the hexose-6-phosphate dehydrogenase (H6PD), the enzyme that produces the cofactor NADPH necessary for the reductase activity of HSD11B1.
Figure 2: A) DDA is a mammalian metabolite produced in normal tissues. DDA is a tumour suppressor metabolite that induces cancer cell re-differentiation into normal-like cells and kills cancer cells via a mechanism of lethal autophagy. DDA inhibits oncosterone biosynthesis at the ChEH step. B) Oncosterone is a tumour promoter that stimulates cancer cell proliferation.
Figure 3: A) ChEH is made of two subunits involved in the late steps of cholesterol biosynthesis. ChEH catalyses the trans-hydration of the epoxide ring 5,6-EC to produce CT which can be subsequently transformed into oncosterone. B) DDA inhibit ChEH which blocks the hydration of 5,6-EC and induces the accumulation of zymostenol.
Figure 4: Snapshot of the 5,6-EC metabolism in normal and pathological breast.
Figure 5: Diagram showing different pharmacological strategies to block the enzymes responsible of oncosterone biosynthesis from 5,6-EC and the receptors that are effectors of oncosterone tumour promoter activity. DDA can control oncosterone biosynthesis and action at the ChEH and LXR levels.