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Identification of a Tumor-Promoter Cholesterol Metabolite in Human Breast Cancers Acting Through the Glucocorticoid Receptor

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Identification of a Tumor-Promoter Cholesterol Metabolite in Human Breast Cancers Acting Through the Glucocorticoid Receptor Identification of a tumor-promoter cholesterol metabolite in human breast cancers acting through the glucocorticoid receptor Maud Voisina,b,1, Philippe de Medinac,1, Arnaud Mallingera,b,1, Florence Dalenca,b,d, Emilie Huc-Claustrea,b, Julie Leignadiera,b, Nizar Serhana,b, Régis Soulesa,b, Grégory Ségalaa,b, Aurélie Mougela,b, Emmanuel Noguera,b,c, Loubna Mhamdic, Elodie Bacquiéa,b, Luigi Iulianoe, Chiara Zerbinatie, Magali Lacroix-Trikid, Léonor Chaltield, Thomas Fillerond, Vincent Cavaillèsf, Talal Al Saatig, Philippe Rochaixd, Raphaelle Duprez-Paumierd, Camille Franchetd, Laetitia Ligath, Fréderic Lopezh, Michel Recorda,b, Marc Poirota,b,2, and Sandrine Silvente-Poirota,b,2 aTeam “Cholesterol Metabolism and Therapeutic Innovations,” Cancer Research Center of Toulouse (CRCT), UMR 1037, Université de Toulouse, CNRS, Inserm, UPS, 31037 Toulouse, France; bUniversité Paul Sabatier, 31062 Toulouse, France; cAffichem, 31400 Toulouse, France; dInstitut Claudius Regaud, Institut Universitaire du Cancer Toulouse-Oncopole, 31059 Toulouse, France; eVascular Biology, Atherothrombosis & Mass Spectrometry Laboratory, Sapienza University of Rome, 04100 Latina, Italy; fl’Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, University of Montpellier, F-34298 Montpellier, France; gINSERM/UPS-US006/Centre Régional d’Exploration Fonctionnelle et Ressources Expérimentales, Service d’Histopathologie, Centre Hospitalier Universitaire Purpan, 31024 Toulouse, France; and hPôle Technologique, Cancer Research Center of Toulouse (CRCT), Plateau Interactions Moléculaires, INSERM-UMR1037, 31037 Toulouse, France Edited by Christopher K. Glass, University of California, San Diego, La Jolla, CA, and approved September 15, 2017 (received for review May 13, 2017) Breast cancer (BC) remains the primary cause of death from cancer ER, Tam also impacts on cholesterol metabolism by targeting among women worldwide. Cholesterol-5,6-epoxide (5,6-EC) metab- cholesterol epoxide hydrolase (ChEH), an enzymatic complex olism is deregulated in BC but the molecular origin of this is formed by two cholesterogenic enzymes, DHCR7 and D8D7I unknown. Here, we have identified an oncometabolism downstream (also known as EBP) (5–7). In normal tissues, ChEH catalyzes of 5,6-EC that promotes BC progression independently of estrogen the hydrolysis of the cholesterol 5,6-epoxides α and β (5,6α-EC receptor α expression. We show that cholesterol epoxide hydrolase and 5,6β-EC) into cholestane-3β,5α,6β-triol (CT) (5, 6, 8). In β α β (ChEH) metabolizes 5,6-EC into cholestane-3 ,5 ,6 -triol, which is normal mammalian tissues, 5,6α-EC reacts with histamine via an β α transformed into the oncometabolite 6-oxo-cholestan-3 ,5 -diol enzyme to produce a tumor suppressor metabolite named den- (OCDO) by 11β-hydroxysteroid-dehydrogenase-type-2 (11βHSD2). β drogenin A (DDA), whose levels are significantly decreased in 11 HSD2 is known to regulate glucocorticoid metabolism by convert- BC compared with normal adjacent tissues (NAT), indicating a ing active cortisol into inactive cortisone. ChEH inhibition and deregulation of this pathway during BC development (3, 4). 11βHSD2 silencing inhibited OCDO production and tumor growth. These data combined suggest a potential role of ChEH activa- Patient BC samples showed significant increased OCDO levels and greater ChEH and 11βHSD2 protein expression compared with nor- tion in BC progression that we explored in the present study. mal tissues. The analysis of several human BC mRNA databases in- Herein, we describe how this led us to discover an oncometabolite, dicated that 11βHSD2 and ChEH overexpression correlated with a higher risk of patient death, highlighting that the biosynthetic path- Significance way producing OCDO is of major importance to BC pathology. OCDO stimulates BC cell growth by binding to the glucocorticoid receptor Cholesterol and its transformation into cholesterol-5,6-epoxides (GR), the nuclear receptor of endogenous cortisol. Interestingly, high (5,6-EC) was long suspected as contributing to breast cancer (BC) GR expression or activation correlates with poor therapeutic re- pathogenesis, before it was found that 5,6-EC metabolism con- sponse or prognosis in many solid tumors, including BC. Targeting trols BC development and is deregulated in breast cancers. the enzymes involved in cholesterol epoxide and glucocorticoid me- Herein, we studied in tumor cells and human samples how 5,6-EC tabolism or GR may be novel strategies to prevent and treat BC. metabolism deregulation promotes tumor progression. We have discovered a pathway in BCs producing an oncometabolite de- breast cancer | oncometabolism | dendrogenin A | therapy | rived from 5,6-EC, through the action of the cortisol-inactivating nuclear receptor enzyme, and identified the glucocorticoid receptor (GR) as the target mediating its proliferative effects. Inhibition of its pro- role for cholesterol in the etiology of cancers has long been duction or GR significantly blocked its action on BC progression. Asuspected, and 5,6-cholesterol epoxides (5,6-EC) were ini- Thus, targeting this oncometabolism and GR represents a new tially thought to be the causative agents. However, recent data opportunity for therapeutic intervention in BCs and potentially have now shown that it is the metabolism of 5,6-EC that is other cancers presenting such deregulations. deregulated in breast cancer (BC), and that this metabolism – Author contributions: M.P. and S.S.-P. designed research; M.V., P.d.M., A. Mallinger, F.D., controls BC development (1 4). To develop novel precision E.H.-C., J.L., N.S., R.S., G.S., A. Mougel, E.N., L.M., E.B., C.Z., M.L.-T., T.A.S., R.D.-P., C.F., L.L., M.R., therapeutic strategies, a deeper understanding of 5,6-EC me- M.P., and S.S.-P. performed research; M.V., P.d.M., A. Mallinger, F.D., E.H.-C., J.L., N.S., R.S., tabolism is required. Indeed, BC remains the most frequent G.S., A. Mougel, E.N., L.M., E.B., L.I., C.Z., M.L.-T., L.C., T.F., V.C., T.A.S., P.R., R.D.-P., C.F., L.L., F.L., M.R., M.P., and S.S.-P. analyzed data; and M.P. and S.S.-P. wrote the paper. cause of death from cancer among women worldwide, despite Conflict of interest statement: P.d.M., E.N., and L.M. are employees of the company the development of targeted therapies, such as Tamoxifen (Tam) Affichem, of which S.S.-P. and M.P. are founders. for treating tumors expressing the estrogen receptor (ER), or This article is a PNAS Direct Submission. agents that target the overexpressed growth factor receptor Published under the PNAS license. HER2 (human epidermal growth factor receptor). These failures 1M.V., P.d.M., and A. Mallinger contributed equally to this work. are explained by the fact that many BC do not respond to these 2To whom correspondence may be addressed. Email: [email protected] or sandrine. therapies or develop resistance, and there are currently no ef- [email protected]. fective targeted therapies to treat tumors that express neither ER This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. nor HER2. In addition to its role as a competitive inhibitor for 1073/pnas.1707965114/-/DCSupplemental. E9346–E9355 | PNAS | Published online October 12, 2017 www.pnas.org/cgi/doi/10.1073/pnas.1707965114 Downloaded by guest on September 29, 2021 6-oxo-cholestan-3β,5α-diol (OCDO), that drives BC progression were treated with 5,6α-EC for 72 h, then lipids were extracted PNAS PLUS through the glucocorticoid receptor (GR). Furthermore, we and submitted to RP-HPLC. Mass spectrometric analysis of the 9- to 11-min RP-HPLC fractions (Fig. 2D) showed peaks of m/z show that OCDO is derived from 5,6-ECs through the action + + of ChEH and the cortisol-inactivating enzyme, 11βHSD2. [M+NH4] = 438.6 and m/z [M+N2H7] = 455.6, corresponding Inhibiting this oncometabolic pathway or GR significantly re- to the mass of CT and consistent with the transformation of duced BC proliferation, suggesting that targeting the actors of 5,6α-EC into CT by ChEH (Fig. 2E). Analysis of the 15- to this pathway could represent new strategies in BC therapy and 17-min RP-HPLC fractions (Fig. 2D) showed peaks of m/z + + = m/z + + = F prevention. [MUM NH4] 436.6 and [MUM N2H7] 453.6 (Fig. 2 ), corresponding to the mass of sOCDO. This confirmed that the Results UM was OCDO (Fig. 2G). Kinetic Analysis of 5,6-EC and CT Metabolism in MCF7 Cells. We first examined the metabolism of [14C]5,6α-EC, [14C]5,6β-EC, and ChEH Inhibition Abrogates OCDO Formation in BC Cells. We next [14C]CT over a 72-h period in the breast cancer cell line MCF7. measured the impact of DDA and other ChEH inhibitors (3, 5) Thin-layer chromatography (TLC) analyses of cell and media on OCDO formation by incubating human MCF7 or MDA-MB- α extracts showed that 5,6α-EC (Fig. 1 A and B) and 5,6β-EC (Fig. 231 tumor cells (expressing or not the ER , respectively) with 14 α 1 C and D) were first converted into CT (retention factor, Rf = [ C]5,6 -EC and the indicated ChEH inhibitors. As shown in A B 0.21) as a result of ChEH activity. However, over time, an un- Fig. 3 and , in both cell lines DDA and the ChEH inhibitors known metabolite (UM), Rf = 0.60, appeared and its level in- tested inhibited OCDO production, including ChEH inhibitors creased at the expense of the 5,6-ECs and CT. Similar experiments known to have antitumor activity and to inhibit ERα, such as performed using [14C]CT alone revealed that the UM was a me- Tam or raloxifene, or to act independently of the ERα, such as tabolite of CT (Fig.
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