title: 27-hydroxycholesterol is an endogenous selective estrogen receptor modulator.
abstract: Selective estrogen receptor (ER) modulators (SERMs) are ER ligands whose relative agonist/antagonist activities vary in a cell- and promoter-dependent manner. The molecular basis underlying this selectivity can be attributed to the ability of these ligands to induce distinct alterations in ER structure leading to differential recruitment of coactivators and corepressors. Whether SERM activity is restricted to synthetic ligands or whether molecules exist in vivo that function in an analogous manner remains unresolved. However, the recent observation that oxysterols bind ER and antagonize the actions of 17beta-estradiol (E2) on the vascular wall suggests that this class of ligands may possess SERM activity. We demonstrate here that 27-hydroxycholesterol (27HC), the most prevalent oxysterol in circulation, functions as a SERM, the efficacy of which varies when assessed on different endpoints. Importantly, 27HC positively regulates both gene transcription and cell proliferation in cellular models of breast cancer. Using combinatorial peptide phage display, we have determined that 27HC induces a unique conformational change in both ERalpha and ERbeta, distinguishing it from E2 and other SERMs. Thus, as with other ER ligands, it appears that the unique pharmacological activity of 27HC relates to its ability to impact ER structure and modulate cofactor recruitment. Cumulatively, these data indicate that 27HC is an endogenous SERM with partial agonist activity in breast cancer cells and suggest that it may influence the pathology of breast cancer. Moreover, given the product-precursor relationship between 27HC and cholesterol, our findings have implications with respect to breast cancer risk in obese/hypercholesteremic individuals.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Carolyn D
authors.initials: CD
authors.lastname: DuSell
authors.forename: Michihisa
authors.initials: M
authors.lastname: Umetani
authors.forename: Philip W
authors.initials: PW
authors.lastname: Shaul
authors.forename: David J
authors.initials: DJ
authors.lastname: Mangelsdorf
authors.forename: Donald P
authors.initials: DP
authors.lastname: McDonnell
mesh_terms: D000595:Amino Acid Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D004305:Dose-Response Relationship, Drug; D004970:Estrone / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D006888:Hydroxycholesterols / Q000737:chemistry / Q000494:pharmacology*; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011401:Promoter Regions, Genetic / Q000235:genetics; D011960:Receptors, Estrogen / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020845:Selective Estrogen Receptor Modulators / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017386:Sequence Homology, Amino Acid; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D006888:Hydroxycholesterols; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D004970:Estrone; C076996:27-hydroxycholesterol