Abstract 1165: Identification of a cholesterol onco-metabolite, promoter of tumor in breast cancers, and of the enzyme involved in its biosynthesis

Abstract

Abstract Breast cancer (BC) is the most common female cancer. Although hormonotherapy (HT), such as Tamoxifen (Tam), is effective for the treatment of most patients with BC expressing estrogen receptors (ER +), resistance to HT is frequent and a number of BC do not express these receptors and do not respond to HT. The mechanisms responsible for these treatment failures remain unclear, indicating that it is necessary to characterize the molecular actors involved in BC etiology, progression and resistance that will help to improve BC phenotyping and treatment efficacy and to identify new therapeutic targets. Recent literature highlights that cholesterol metabolism can produce new targets for cancer progression and resistance. We characterized a new pathway in cholesterol metabolism at the level of Cholesterol Epoxide Hydrolase (ChEH). ChEH selectively catalyses the hydrolysis of cholesterol 5,6-epoxides (EC) into cholestan-3β,5α,6β-triol (CT) and is a high affinity target of anti-cancer compounds, such as Tam (de Medina et al, PNAS, 2010). We showed that the enzymatic transformation of EC leads to the production of a tumor suppressor metabolite, dendrogenin A (DDA), involved in the control of cell differentiation and growth, and reported that DDA production is decreased in BC compared with normal tissue (de Medina et al, Nature Commun, 2013, Silvente-Poirot et al, Science, 2014). The aim of the present study was to characterize further the deregulations of this metabolism and to determine the potential role of ChEH activation in BC progression. We established that the activity of ChEH in BC cells generates an unexpected metabolite from CT. By using RP-HPLC and GC-MS, we determined this unknown metabolite to be the oxysterol: 6-oxo-cholestan-3β,5α-diol (OCDO). We characterized that OCDO stimulates proliferation in vitro and in vivo of various BC cells expressing or not the ER. Interestingly, OCDO formation in tumor cells and tumors grafted into mice was strongly inhibited by ChEH inhibitors known to have anti-tumor activity such as Tam, PBPE or DDA. We identified the enzyme responsible for the transformation of CT into OCDO (OCDO synthase). The knock down of OCDO synthase expression using specific shRNA decreased OCDO production and proliferation of MCF7 tumor implanted into mice, and OCDO treatment reversed these inhibitions. Moreover, immunohistology analyses of patient samples indicated that OCDO synthase was overexpressed in tumors compared with normal tissues. In conclusion, the data obtained indicate that deregulations of the metabolism of cholesterol 5,6-epoxides occur in ER-positive and ER-negative tumor cells to favor OCDO production, an onco-metabolite promoter of BC. Therefore, OCDO, EC and CT production as well as the expression of the enzymes producing these metabolites could be markers of BC and of the efficacy of anti-cancer compounds such as Tam or DDA. Citation Format: Maud Voisin, Philippe de Medina, Michael R. Paillasse, Magali Lacroix-Triki, Florence Dalenc, Marc Poirot, Sandrine Silvente-Poirot. Identification of a cholesterol onco-metabolite, promoter of tumor in breast cancers, and of the enzyme involved in its biosynthesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1165. doi:10.1158/1538-7445.AM2015-1165