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27-Hydroxycholesterol Is an Endogenous Selective Estrogen Receptor Modulator

Department of Pharmacology and Cancer Biology (C.D.D., D.P.M.), Duke University Medical Center, Durham, North Carolina 27710; and Department of Pharmacology and Howard Hughes Medical Institute (M.U., D.J.M.) and Department of Pediatrics (P.W.S.), University of Texas Southwestern Medical Center, Dallas, Texas 75390

Address all correspondence and requests for reprints to: Donald P. McDonnell, Ph.D., Duke University Medical Center, Pharmacology and Cancer Biology, Box 3813, Durham, North Carolina 27710. E-mail: donald.mcdonnell{at}duke.edu.

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 17β-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 ER and ERβ, 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.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ  |  PR

Coregulators:   Cyclin D1  |  SRC-1  |  GRIP1  |  AIB1  |  ASC-2

Ligands:   17β-Estradiol  |  4-Hydroxytamoxifen  |  Raloxifene  |  Fulvestrant