| Added by | Cavailles |
|---|---|
| Group name | EquipeVC |
| Item Type | Journal Article |
| Title | Identification of a tumor-promoter cholesterol metabolite in human breast cancers acting through the glucocorticoid receptor |
| Creator | Voisin et al. |
| Author | Maud Voisin |
| Author | Philippe de Medina |
| Author | Arnaud Mallinger |
| Author | Florence Dalenc |
| Author | Emilie Huc-Claustre |
| Author | Julie Leignadier |
| Author | Nizar Serhan |
| Author | Régis Soules |
| Author | Grégory Ségala |
| Author | Aurélie Mougel |
| Author | Emmanuel Noguer |
| Author | Loubna Mhamdi |
| Author | Elodie Bacquié |
| Author | Luigi Iuliano |
| Author | Chiara Zerbinati |
| Author | Magali Lacroix-Triki |
| Author | Léonor Chaltiel |
| Author | Thomas Filleron |
| Author | Vincent Cavaillès |
| Author | Talal Al Saati |
| Author | Philippe Rochaix |
| Author | Raphaelle Duprez-Paumier |
| Author | Camille Franchet |
| Author | Laetitia Ligat |
| Author | Fréderic Lopez |
| Author | Michel Record |
| Author | Marc Poirot |
| Author | Sandrine Silvente-Poirot |
| 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 ? expression. We show that cholesterol epoxide hydrolase (ChEH) metabolizes 5,6-EC into cholestane-3?,5?,6?-triol, which is transformed into the oncometabolite 6-oxo-cholestan-3?,5?-diol (OCDO) by 11?-hydroxysteroid-dehydrogenase-type-2 (11?HSD2). 11?HSD2 is known to regulate glucocorticoid metabolism by converting active cortisol into inactive cortisone. ChEH inhibition and 11?HSD2 silencing inhibited OCDO production and tumor growth. Patient BC samples showed significant increased OCDO levels and greater ChEH and 11?HSD2 protein expression compared with normal tissues. The analysis of several human BC mRNA databases indicated that 11?HSD2 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. |
| Publication | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 114 |
| Issue | 44 |
| Pages | E9346-E9355 |
| Date | 10 31, 2017 |
| Journal Abbr | Proc. Natl. Acad. Sci. U.S.A. |
| Language | eng |
| DOI | 10.1073/pnas.1707965114 |
| ISSN | 1091-6490 |
| Library Catalog | PubMed |
| Extra | PMID: 29078321 PMCID: PMC5676900 |
| Tags | 11-beta-Hydroxysteroid Dehydrogenase Type 2, Animals, breast cancer, Breast Neoplasms, Carcinogens, Cell Line, Cell Line, Tumor, Cholesterol, dendrogenin A, Epoxide Hydrolases, Estrogen Receptor alpha, Female, HEK293 Cells, Humans, MCF-7 Cells, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Nude, nuclear receptor, oncometabolism, original, Receptors, Glucocorticoid, RNA, Messenger, therapy |
| Date Added | 2019/05/16 - 11:22:17 |
| Date Modified | 2019/05/16 - 11:41:42 |
| Notes and Attachments | PubMed entry (Attachment) Texte intégral (Attachment) |
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