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Biochem Pharmacol. 2017 Nov 15;144:18-28. doi: 10.1016/j.bcp.2017.06.120. Epub 2017 Jun 19.

Improving the efficacy of hormone therapy in breast cancer: The role of cholesterol metabolism in SERM-mediated autophagy, cell differentiation and death.

Author information

1
Cancer Research Center of Toulouse, UMR 1037INSERM-University of Toulouse, Toulouse, France.
2
Cancer Research Center of Toulouse, UMR 1037INSERM-University of Toulouse, Toulouse, France; Institut Claudius Regaud, Institut Universitaire du Cancer-Oncopole, Toulouse, France.
3
Cancer Research Center of Toulouse, UMR 1037INSERM-University of Toulouse, Toulouse, France. Electronic address: marc.poirot@inserm.fr.
4
Cancer Research Center of Toulouse, UMR 1037INSERM-University of Toulouse, Toulouse, France. Electronic address: sandrine.poirot@inserm.fr.

Abstract

Breast cancer (BC) is one of the most common female cancers in the world, with estrogen receptor (ER)-positive BC the most frequent subtype. Tamoxifen (Tam) is an effective drug that competitively binds to the ER and is routinely used for the treatment of ER-positive BC. However, a number of ER-positive BC do not respond to Tam treatment and acquired resistance is often observed, constituting a major challenge for extending patient life expectancy. The mechanisms responsible for these treatment failures remain unclear, indicating the requirement for other targets and better predictors for patient response to Tam. One of Tam's off-targets of interest is the microsomal antiestrogen binding site (AEBS), a multiproteic complex made up of the cholesterol-5,6-epoxide hydrolase (ChEH) enzymes that are involved in the late stages of cholesterol biosynthesis. Tam and other selective ER modulators stimulate oxidative stress and inhibit the ChEH subunits at pharmacological doses, triggering the production and accumulation of cholesterol-5,6-epoxide metabolites responsible for BC cell differentiation and death. However, inhibition of the cholesterogenic activity of the AEBS subunits also induces the accumulation of sterol precursors, which triggers a survival autophagy to impair Tam's efficacy. Altogether, these studies have highlighted the involvement of cholesterol metabolism in the pharmacology of Tam that has provided new clues on how to improve its therapeutic efficacy in both BC and other cancers as well as offering a new rationale for developing more efficient drugs for BC treatment.

KEYWORDS:

17β-estradiol (PubChem CID: 5757); 4-hydroxytamoxifen (PubChem CID: 449459); 5,6-Epoxycholesterol; 5,6α-epoxycholesterol (PubChem CID: 227037); 5,6β-epoxycholesterol (PubChem CID: 108109); 7-dehydrocholesterol (PubChem CID: 439423); AEBS; Breast cancer; ICI 164,684 (PubChem CID: 104772); ICI 182,780 (PubChem CID: 44307470); MER29, triparanol (PubChem CID: 6536); PBPE (PubChem CID: 71311880); RU 58,668 (PubChemCID: 119604); Tamoxifen; Zymostenol; bazedoxifene (PubChem CID: 154257); boxidine (PubChem CID: 31742); cholesterol (PubChem CID: 5997); clomiphene (PubChem CID: 1548953); dendrogenin A (PubChem CID: 9806490); desmosterol: (PubChem CID: 439577); histamine (PubChem CID: 774); lasofoxifene (PubChem CID: 216416); raloxifene (PubChem CID: 5035); tamoxifen (PubChem CID: 2733526); tesmilifene (PubChem CID: 108092); toremifene (PubChem CID: 3005573); zymostenol (PubChem CID: 101770); zymosterol (PubChem CID: 92746)

PMID:
28642035
DOI:
10.1016/j.bcp.2017.06.120
[Indexed for MEDLINE]

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