RESUMO
Covalent modifications of histones play a crucial role in the regulation of gene expression. Histone H2B monoubiquitination has mainly been described as a regulator of transcription elongation, but its role in transcription initiation is poorly documented. We investigated the role of this histone mark (H2Bub1) on different inducible enhancers, in particular those regulated by estrogen receptor α, by loss- and gain-of-function experiments with the specific E3-ubiquitin ligase complex of H2B: RNF20/RNF40. RNF20/RNF40 overexpression causes repression of the induced activity of these enhancers. Genome-wide profiles show that H2Bub1 levels are negatively correlated with the accessibility of enhancers to transcriptional activators. We found that the chromatin association of histone variant H2A.Z, which is evicted from enhancers for transcriptional activation, is stabilized by H2Bub1 by impairing access of the chromatin remodeler INO80. We propose that H2Bub1 acts as a gatekeeper of H2A.Z eviction and activation of inducible enhancers.
Assuntos
Cromatina/química , DNA Helicases/genética , Histonas/genética , Ubiquitina-Proteína Ligases/genética , ATPases Associadas a Diversas Atividades Celulares , Linhagem Celular Tumoral , Cromatina/metabolismo , Montagem e Desmontagem da Cromatina , DNA Helicases/metabolismo , Proteínas de Ligação a DNA , Elementos Facilitadores Genéticos , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Perfilação da Expressão Gênica , Genes Reporter , Células HEK293 , Histonas/metabolismo , Humanos , Luciferases/genética , Luciferases/metabolismo , Transdução de Sinais , Ativação Transcricional , Ubiquitina-Proteína Ligases/metabolismo , UbiquitinaçãoRESUMO
BACKGROUND: The molecular chaperone TRAP1, the mitochondrial isoform of cytosolic HSP90, remains poorly understood with respect to its pivotal role in the regulation of mitochondrial metabolism. Most studies have found it to be an inhibitor of mitochondrial oxidative phosphorylation (OXPHOS) and an inducer of the Warburg phenotype of cancer cells. However, others have reported the opposite, and there is no consensus on the relevant TRAP1 interactors. This calls for a more comprehensive analysis of the TRAP1 interactome and of how TRAP1 and mitochondrial metabolism mutually affect each other. RESULTS: We show that the disruption of the gene for TRAP1 in a panel of cell lines dysregulates OXPHOS by a metabolic rewiring that induces the anaplerotic utilization of glutamine metabolism to replenish TCA cycle intermediates. Restoration of wild-type levels of OXPHOS requires full-length TRAP1. Whereas the TRAP1 ATPase activity is dispensable for this function, it modulates the interactions of TRAP1 with various mitochondrial proteins. Quantitatively by far, the major interactors of TRAP1 are the mitochondrial chaperones mtHSP70 and HSP60. However, we find that the most stable stoichiometric TRAP1 complex is a TRAP1 tetramer, whose levels change in response to both a decline and an increase in OXPHOS. CONCLUSIONS: Our work provides a roadmap for further investigations of how TRAP1 and its interactors such as the ATP synthase regulate cellular energy metabolism. Our results highlight that TRAP1 function in metabolism and cancer cannot be understood without a focus on TRAP1 tetramers as potentially the most relevant functional entity.
Assuntos
Proteínas de Choque Térmico HSP90/genética , Homeostase , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Chaperonas Moleculares/genética , Fosforilação Oxidativa , Linhagem Celular , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Chaperonas Moleculares/metabolismoRESUMO
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-3ß,5α,6ß-triol, which is transformed into the oncometabolite 6-oxo-cholestan-3ß,5α-diol (OCDO) by 11ß-hydroxysteroid-dehydrogenase-type-2 (11ßHSD2). 11ßHSD2 is known to regulate glucocorticoid metabolism by converting active cortisol into inactive cortisone. ChEH inhibition and 11ßHSD2 silencing inhibited OCDO production and tumor growth. Patient BC samples showed significant increased OCDO levels and greater ChEH and 11ßHSD2 protein expression compared with normal tissues. The analysis of several human BC mRNA databases indicated that 11ßHSD2 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.
Assuntos
Neoplasias da Mama/metabolismo , Carcinógenos/metabolismo , Colesterol/metabolismo , Receptores de Glucocorticoides/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Animais , Linhagem Celular , Linhagem Celular Tumoral , Colesterol/análogos & derivados , Epóxido Hidrolases/metabolismo , Receptor alfa de Estrogênio/metabolismo , Feminino , Células HEK293 , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , RNA Mensageiro/metabolismoRESUMO
The estrogen receptor α (ERα) is a transcription factor that can be directly activated by estrogen or indirectly by other signaling pathways. We previously reported that activation of the unliganded ERα by cAMP is mediated by phosphorylation of the transcriptional coactivator CARM1 by protein kinase A (PKA), allowing CARM1 to bind ERα directly. This being insufficient by itself to activate ERα, we looked for additional factors and identified the histone H3 demethylase LSD1 as a substrate of PKA and an important mediator of this signaling crosstalk as well as of the response to estrogen. Surprisingly, ERα engages not only LSD1, but its partners of the CoREST corepressor complex and the molecular chaperone Hsp90. The recruitment of Hsp90 to promote ERα transcriptional activity runs against the steroid receptor paradigm and suggests that it might be involved as an assembly factor or scaffold. In a breast cancer cell line, which is resistant to the anti-estrogen tamoxifen because of constitutively activated PKA, some interactions are constitutive and drug combinations partially rescue tamoxifen sensitivity. In ERα-positive breast cancer patients, high expression of the genes encoding some of these factors correlates with poor prognosis. Thus, these mechanisms might contribute to ERα-driven breast cancer.
Assuntos
Proteínas Correpressoras/metabolismo , AMP Cíclico/farmacologia , Receptor alfa de Estrogênio/genética , Estrogênios/farmacologia , Histona Desmetilases/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Citoplasma/efeitos dos fármacos , Citoplasma/metabolismo , Receptor alfa de Estrogênio/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/metabolismo , Histona Desacetilases/metabolismo , Humanos , Ligantes , Modelos Biológicos , Fosforilação/efeitos dos fármacos , Prognóstico , Proteína-Arginina N-Metiltransferases/metabolismo , Especificidade por Substrato/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacos , Resultado do TratamentoRESUMO
The microsomal antiestrogen binding site (AEBS) is a high-affinity target for the antitumor drug tamoxifen and its cognate ligands that mediate breast cancer cell differentiation and apoptosis. The AEBS, a hetero-oligomeric complex composed of 3beta-hydroxysterol-Delta8-Delta7-isomerase (D8D7I) and 3beta-hydroxysterol-Delta7-reductase (DHCR7), binds different structural classes of ligands, including ring B oxysterols. These oxysterols are inhibitors of cholesterol-5,6-epoxide hydrolase (ChEH), a microsomal epoxide hydrolase that has yet to be molecularly identified. We hypothesized that the AEBS and ChEH might be related entities. We show that the substrates of ChEH, cholestan-5alpha,6alpha-epoxy-3beta-ol (alpha-CE) and cholestan-5beta,6beta-epoxy-3beta-ol (beta-CE), and its product, cholestane-3beta,5alpha,6beta-triol (CT), are competitive ligands of tamoxifen binding to the AEBS. Conversely, we show that each AEBS ligand is an inhibitor of ChEH activity, and that there is a positive correlation between these ligands' affinity for the AEBS and their potency to inhibit ChEH (r2=0.95; n=39; P<0.0001). The single expression of D8D7I or DHCR7 in COS-7 cells slightly increased ChEH activity (1.8- and 2.6-fold), whereas their coexpression fully reconstituted ChEH, suggesting that the formation of a dimer is required for ChEH activity. Similarly, the single knockdown of D8D7I or DHCR7 using siRNA partially inhibited ChEH in MCF-7 cells, whereas the knockdown of both D8D7I and DHCR7 abolished ChEH activity by 92%. Taken together, our findings strongly suggest that the AEBS carries out ChEH activity and establish that ChEH is a new target for drugs of clinical interest, polyunsaturated fatty acids and ring B oxysterols.
Assuntos
Epóxido Hidrolases/antagonistas & inibidores , Epóxido Hidrolases/metabolismo , Ligantes , Esteróis/farmacologia , Animais , Sítios de Ligação , Ligação Competitiva , Biocatálise/efeitos dos fármacos , Células COS , Chlorocebus aethiops , Colesterol/química , Colesterol/metabolismo , Antagonistas de Estrogênios/química , Antagonistas de Estrogênios/metabolismo , Cinética , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Ensaio Radioligante , Ratos , Receptores de Estrogênio/metabolismo , Esteróis/química , Tamoxifeno/química , Tamoxifeno/metabolismoRESUMO
Dendrogenin A (DDA) is a mammalian cholesterol metabolite that displays potent antitumor properties on acute myeloid leukemia (AML). DDA triggers lethal autophagy in cancer cells through a biased activation of the oxysterol receptor LXRß, and the inhibition of a sterol isomerase. We hypothesize that DDA could potentiate the activity of an anticancer drug acting through a different molecular mechanism, and conducted in vitro and in vivo combination tests on AML cell lines and patient primary tumors. We report here results from tests combining DDA with antimetabolite cytarabine (Ara-C), one of the main drugs used for AML treatment worldwide. We demonstrated that DDA potentiated and sensitized AML cells, including primary patient samples, to Ara-C in vitro and in vivo. Mechanistic studies revealed that this sensitization was LXRß-dependent and was due to the activation of lethal autophagy. This study demonstrates a positive in vitro and in vivo interaction between DDA and Ara-C, and supports the clinical evaluation of DDA in combination with Ara-C for the treatment of AML.
RESUMO
In response to extracellular signals, many signalling proteins associated with the plasma membrane are sorted into endosomes. This involves endosomal fusion, which depends on the complexes HOPS and CORVET. Whether and how their subunits themselves modulate signal transduction is unknown. We show that Vps11 and Vps18 (Vps11/18), two common subunits of the HOPS/CORVET complexes, are E3 ubiquitin ligases. Upon overexpression of Vps11/Vps18, we find perturbations of ubiquitination in signal transduction pathways. We specifically demonstrate that Vps11/18 regulate several signalling factors and pathways, including Wnt, estrogen receptor α (ERα), and NFκB. For ERα, we demonstrate that the Vps11/18-mediated ubiquitination of the scaffold protein PELP1 impairs the activation of ERα by c-Src. Thus, proteins involved in membrane traffic, in addition to performing their well-described role in endosomal fusion, fine-tune signalling in several different ways, including through ubiquitination.
Assuntos
Proteínas Correpressoras/metabolismo , Endossomos/metabolismo , Fatores de Transcrição/metabolismo , Complexos Ubiquitina-Proteína Ligase/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Proteína Tirosina Quinase CSK , Receptor alfa de Estrogênio/metabolismo , Células HEK293 , Humanos , Células MCF-7 , NF-kappa B/metabolismo , Transdução de Sinais/fisiologia , Ubiquitinação/fisiologia , Proteínas Wnt/metabolismo , Quinases da Família src/metabolismoRESUMO
Dendrogenin A (DDA) is a mammalian metabolite that displays anticancer and chemopreventive properties in mice. At the cancer cell level, DDA induces differentiation and death. We investigated herein the nature of DDA cytoxicity in cancer cells. We showed that DDA triggers biochemical and cellular features of macroautophagy/autophagy and that autophagy is cytotoxic. DDA induces both the accumulation of pro-lysosomal sterols and stimulates the expression of regulators of autophagy such as NR4A, LC3 and TFEB through binding to the liver X receptor (LXR), a ligand-dependent transcription factor consisting of 2 isoforms, NR1H2 and NR1H3. These effects are not observed with canonical LXR agonists such as the oxysterol 22(R)-hydroxycholesterol or the synthetic molecules T0901317 and GW3965. DDA effects were measured on melanoma and acute myeloid leukemia cells including patient-derived leukemia cells in vitro and in vivo. Importantly the induction of lethal autophagy kills cells independently of their cytogenetic subgroups and does not differentiate bulk cancer cells from cancer cell progenitors. Together these data show that DDA drives LXR to induce the expression of autophagic genes leading to cancer cells death. This opens up new perspectives for cancer treatment.
Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Benzoatos/farmacologia , Benzilaminas/farmacologia , Hidrocarbonetos Fluorados/farmacologia , Sulfonamidas/farmacologia , Animais , Linhagem Celular Tumoral , Ligantes , Receptores X do Fígado/efeitos dos fármacos , Lisossomos/efeitos dos fármacos , Camundongos , Neoplasias/tratamento farmacológicoRESUMO
Recently, we reported the unexpected finding that the monoubiquitination of histone H2B (H2Bub1) regulates inducible enhancers. Here, we propose a conceptual framework to reconcile the apparently discrepant roles of H2Bub1 in transcription initiation and elongation, and we discuss how H2Bub1 could regulate cellular processes linked to non-coding transcription.
Assuntos
Histonas/metabolismo , Sequências Reguladoras de Ácido Nucleico , Animais , Metilação de DNA , Estradiol/farmacologia , Receptor alfa de Estrogênio/metabolismo , Histonas/genética , Humanos , Células MCF-7 , NF-kappa B/metabolismo , RNA/biossíntese , RNA Polimerase II/metabolismo , Sequências Reguladoras de Ácido Nucleico/efeitos dos fármacos , Elongação da Transcrição Genética , Iniciação da Transcrição Genética , Ubiquitinação/efeitos dos fármacosRESUMO
Dendrogenin A (DDA) is a newly discovered cholesterol metabolite with tumor suppressor properties. Here, we explored its efficacy and mechanism of cell death in melanoma and acute myeloid leukemia (AML). We found that DDA induced lethal autophagy in vitro and in vivo, including primary AML patient samples, independently of melanoma Braf status or AML molecular and cytogenetic classifications. DDA is a partial agonist on liver-X-receptor (LXR) increasing Nur77, Nor1, and LC3 expression leading to autolysosome formation. Moreover, DDA inhibited the cholesterol biosynthesizing enzyme 3ß-hydroxysterol-Δ8,7-isomerase (D8D7I) leading to sterol accumulation and cooperating in autophagy induction. This mechanism of death was not observed with other LXR ligands or D8D7I inhibitors establishing DDA selectivity. The potent anti-tumor activity of DDA, its original mechanism of action and its low toxicity support its clinical evaluation. More generally, this study reveals that DDA can direct control a nuclear receptor to trigger lethal autophagy in cancers.
Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Colestanóis/farmacologia , Imidazóis/farmacologia , Leucemia Mieloide Aguda , Receptores X do Fígado/efeitos dos fármacos , Melanoma , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Agonismo Parcial de Drogas , Expressão Gênica/efeitos dos fármacos , Células HEK293 , Células HL-60 , Humanos , Técnicas In Vitro , Receptores X do Fígado/metabolismo , Melanoma Experimental , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Proteínas de Membrana Transportadoras/genética , Camundongos , Proteínas Associadas aos Microtúbulos/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/genética , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/efeitos dos fármacos , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genéticaRESUMO
We have recently discovered the existence of 5α-Hydroxy-6ß-[2-(1H-imidazol-4-yl)ethylamino]cholestan-3ß-ol, called Dendrogenin A (DDA), as the first endogenous steroidal alkaloid ever described in mammals. We found that the DDA content of tumors and cancer cell lines was low or absent compared with normal cells showing that a deregulation in DDA biosynthesis was associated with cancer and therefore suggesting that DDA could represent a metabolomic cancer biomarker. This prompted us to produce antibodies that selectively recognize DDA. For this purpose, the hapten 5α-hydroxy-6ß-[2-(1H-imidazol-4-yl)ethylamino]cholestan-3ß-o-hemisuccinate with a carboxylic spacer arm attached to the 3ß-hydroxyl group of DDA was synthesized. The hapten was coupled to bovine serum albumin and keyhole limpet hemocyanin for antibody production to develop an enzyme-linked immunosorbent assay (ELISA). The protein conjugates were injected into BALB/c mice to raise antibodies. The monoclonal antibodies that were secreted from the hybridoma cell lines established were assessed with indirect ELISA by competitive assays using dilutions of a DDA standard. The antibodies from the selected hybridomas had an IC(50) value ranging from 0.8 to 425 ng/ml. Three antibodies showed no cross-reactivity with structurally related compounds including histamine, cholesterol, ring B oxysterols and a regio-isomer of DDA. In this study, high-affinity and selective antibodies against DDA were produced for the first time, and a competitive indirect ELISA was developed.
Assuntos
Anticorpos/metabolismo , Produtos Biológicos/análise , Colestanol/análise , Colestanóis/análise , Colestanóis/química , Ensaio de Imunoadsorção Enzimática/métodos , Haptenos/química , Imidazóis/análise , Espermidina/análogos & derivados , Animais , Anticorpos/imunologia , Produtos Biológicos/imunologia , Técnicas de Química Sintética , Colestanol/imunologia , Colestanóis/imunologia , Reações Cruzadas , Feminino , Haptenos/imunologia , Hibridomas/citologia , Imidazóis/imunologia , Soros Imunes/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Espermidina/química , Espermidina/imunologiaRESUMO
Tamoxifen (Tam) is a selective estrogen receptor modulator (SERM) that remains one of the major drugs used in the hormonotherapy of breast cancer (BC). In addition to its SERM activity, we recently showed that the oxidative metabolism of cholesterol plays a role in its anticancer pharmacology. We established that these effects were not regulated by the ER but by the microsomal antiestrogen binding site/cholesterol-5,6-epoxide hydrolase complex (AEBS/ChEH). The present study aimed to identify the oxysterols that are produced under Tam treatment and to define their mechanisms of action. Tam and PBPE (a selective AEBS/ChEH ligand) stimulated the production and the accumulation of 5,6α-epoxy-cholesterol (5,6α-EC), 5,6α-epoxy-cholesterol-3ß-sulfate (5,6-ECS), 5,6ß-epoxy-cholesterol (5,6ß-EC) in MCF-7 cells through a ROS-dependent mechanism, by inhibiting ChEH and inducing sulfation of 5,6α-EC by SULT2B1b. We showed that only 5,6α-EC was responsible for the induction of triacylglycerol (TAG) biosynthesis by Tam and PBPE, through the modulation of the oxysterol receptor LXRß. The cytotoxicity mediated by Tam and PBPE was triggered by 5,6ß-EC through an LXRß-independent route and by 5,6-ECS through an LXRß-dependent mechanism. The importance of SULT2B1b was confirmed by its ectopic expression in the SULT2B1b(-) MDA-MB-231 cells, which became sensitive to 5,6α-EC, Tam or PBPE at a comparable level to MCF-7 cells. This study established that 5,6-EC metabolites contribute to the anticancer pharmacology of Tam and highlights a novel signaling pathway that points to a rationale for re-sensitizing BC cells to Tam and AEBS/ChEH ligands.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Colesterol/análogos & derivados , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Tamoxifeno/farmacologia , Sítios de Ligação , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Colesterol/metabolismo , Epóxido Hidrolases/metabolismo , Moduladores de Receptor Estrogênico/metabolismo , Feminino , Humanos , Ligantes , Receptores X do Fígado , Receptores Nucleares Órfãos/metabolismo , Oxirredução , Pirrolidinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Sulfotransferases/metabolismo , Triglicerídeos/biossínteseRESUMO
We previously synthesized dendrogenin A and hypothesized that it could be a natural metabolite occurring in mammals. Here we explore this hypothesis and report the discovery of dendrogenin A in mammalian tissues and normal cells as an enzymatic product of the conjugation of 5,6α-epoxy-cholesterol and histamine. Dendrogenin A was not detected in cancer cell lines and was fivefold lower in human breast tumours compared with normal tissues, suggesting a deregulation of dendrogenin A metabolism during carcinogenesis. We established that dendrogenin A is a selective inhibitor of cholesterol epoxide hydrolase and it triggered tumour re-differentiation and growth control in mice and improved animal survival. The properties of dendrogenin A and its decreased level in tumours suggest a physiological function in maintaining cell integrity and differentiation. The discovery of dendrogenin A reveals a new metabolic pathway at the crossroads of cholesterol and histamine metabolism and the existence of steroidal alkaloids in mammals.
Assuntos
Antineoplásicos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Colestanóis/farmacologia , Colesterol/metabolismo , Histamina/metabolismo , Imidazóis/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Líquidos Corporais/metabolismo , Encéfalo/metabolismo , Linhagem Celular Tumoral , Colestanóis/química , Colestanóis/uso terapêutico , Epóxido Hidrolases/antagonistas & inibidores , Epóxido Hidrolases/metabolismo , Feminino , Humanos , Imidazóis/química , Imidazóis/uso terapêutico , Imunocompetência/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Linfócitos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Receptores de Estrogênio/metabolismo , Análise de Sobrevida , Extratos de TecidosRESUMO
Tamoxifen is one of the major drugs used for the hormonotherapy of estrogen receptor positive breast cancers. However, its therapeutic efficacy can be limited by acquired resistance and tumor recurrence can occur after several years of treatment. Tamoxifen is known as the prototypical modulator of estrogen receptors, but other targets have been identified that could account for its pharmacology. In particular, tamoxifen binds with high affinity to the microsomal antiestrogen binding site (AEBS) and inhibits cholesterol esterification at therapeutic doses. We have recently shown that the AEBS was a hetero-oligomeric complex composed of 3ß-hydroxysterol-Δ(8)-Δ(7)-isomerase and 3ß-hydroxysterol-Δ(7)-reductase, that binds different structural classes of ligands, including selective estrogen receptor modulators, several sigma receptor ligands, poly-unsaturated fatty acids and ring B oxysterols. We established a link between the modulation of cholesterol metabolism by tamoxifen and other AEBS ligands and their capacity to induce breast cancer cell differentiation, apoptosis and autophagy. Moreover, we showed that the AEBS carries out cholesterol-5,6-epoxide hydrolase activity and established that cholesterol-5,6-epoxide hydrolase is a new target for tamoxifen and other AEBS ligands. Finally in this review, we report on recent data from the literature showing how the modulation of cholesterol and oxysterol metabolism can be linked to the antitumor and chemopreventive properties of tamoxifen, and give new perspectives to improve the clinical outcome of the hormonotherapy of breast cancers.