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

Voisin M, de Medina P, Mallinger A, Dalenc F, Huc-Claustre E, Leignadier J, Serhan N, Soules R, Ségala G, Mougel A, Noguer E, Mhamdi L, Bacquié E, Iuliano L, Zerbinati C, Lacroix-Triki M, Chaltiel L, Filleron T, Cavaillès V, Al Saati T, Rochaix P, Duprez-Paumier R, Franchet C, Ligat L, Lopez F, Record M, Poirot M, Silvente-Poirot S. 2017 Oct 12

Proc Natl Acad Sci U S A. 2017 Oct 31;114(44):E9346-E9355. doi: 10.1073/pnas.1707965114. Epub 2017 Oct 12.

Breast cancer (BC) remains the primary cause of death from cancer among women worldwide. Cholesterol-5,6-epoxide (5,6-EC) metabolism is deregulated in BC but the molecular origin of this is unknown. Here, we have identified an oncometabolism downstream of 5,6-EC that promotes BC progression independently of estrogen receptor α expression. We show that cholesterol epoxide hydrolase (ChEH) metabolizes 5,6-EC into cholestane-3β,5α,6β-triol, which is transformed into the oncometabolite 6-oxo-cholestan-3β,5α-diol (OCDO) by 11β-hydroxysteroid-dehydrogenase-type-2 (11βHSD2). 11βHSD2 is known to regulate glucocorticoid metabolism by converting active cortisol into inactive cortisone. ChEH inhibition and 11βHSD2 silencing inhibited OCDO production and tumor growth. Patient BC samples showed significant increased OCDO levels and greater ChEH and 11βHSD2 protein expression compared with normal tissues. The analysis of several human BC mRNA databases indicated that 11βHSD2 and ChEH overexpression correlated with a higher risk of patient death, highlighting that the biosynthetic pathway producing OCDO is of major importance to BC pathology. OCDO stimulates BC cell growth by binding to the glucocorticoid receptor (GR), the nuclear receptor of endogenous cortisol. Interestingly, high GR expression or activation correlates with poor therapeutic response or prognosis in many solid tumors, including BC. Targeting the enzymes involved in cholesterol epoxide and glucocorticoid metabolism or GR may be novel strategies to prevent and treat BC.

KEYWORDS:

breast cancer; dendrogenin A; nuclear receptor; oncometabolism; therapy