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

Abstract : 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.
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https://hal.umontpellier.fr/hal-02316171
Contributeur : Nathalie Salvy-Cordoba <>
Soumis le : mardi 15 octobre 2019 - 10:25:48
Dernière modification le : mercredi 11 décembre 2019 - 16:16:03

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Maud Voisin, Philippe de Medina, Arnaud Mallinger, Florence Dalenc, Emilie Huc-Claustre, et al.. Identification of a tumor-promoter cholesterol metabolite in human breast cancers acting through the glucocorticoid receptor. Proceedings of the National Academy of Sciences of the United States of America , National Academy of Sciences, 2017, 114 (44), pp.E9346-E9355. ⟨10.1073/pnas.1707965114⟩. ⟨hal-02316171⟩

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