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.