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27-hydroxycholesterol is an endogenous selective estrogen receptor modulator.

Publication ,  Journal Article
DuSell, CD; Umetani, M; Shaul, PW; Mangelsdorf, DJ; McDonnell, DP
Published in: Mol Endocrinol
January 2008

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.

Duke Scholars

Published In

Mol Endocrinol

DOI

ISSN

0888-8809

Publication Date

January 2008

Volume

22

Issue

1

Start / End Page

65 / 77

Location

United States

Related Subject Headings

  • Transcription, Genetic
  • Sequence Homology, Amino Acid
  • Selective Estrogen Receptor Modulators
  • Reverse Transcriptase Polymerase Chain Reaction
  • Receptors, Estrogen
  • Promoter Regions, Genetic
  • Molecular Structure
  • Molecular Sequence Data
  • Hydroxycholesterols
  • Humans
 

Citation

APA
Chicago
ICMJE
MLA
NLM
DuSell, C. D., Umetani, M., Shaul, P. W., Mangelsdorf, D. J., & McDonnell, D. P. (2008). 27-hydroxycholesterol is an endogenous selective estrogen receptor modulator. Mol Endocrinol, 22(1), 65–77. https://doi.org/10.1210/me.2007-0383
DuSell, Carolyn D., Michihisa Umetani, Philip W. Shaul, David J. Mangelsdorf, and Donald P. McDonnell. “27-hydroxycholesterol is an endogenous selective estrogen receptor modulator.Mol Endocrinol 22, no. 1 (January 2008): 65–77. https://doi.org/10.1210/me.2007-0383.
DuSell CD, Umetani M, Shaul PW, Mangelsdorf DJ, McDonnell DP. 27-hydroxycholesterol is an endogenous selective estrogen receptor modulator. Mol Endocrinol. 2008 Jan;22(1):65–77.
DuSell, Carolyn D., et al. “27-hydroxycholesterol is an endogenous selective estrogen receptor modulator.Mol Endocrinol, vol. 22, no. 1, Jan. 2008, pp. 65–77. Pubmed, doi:10.1210/me.2007-0383.
DuSell CD, Umetani M, Shaul PW, Mangelsdorf DJ, McDonnell DP. 27-hydroxycholesterol is an endogenous selective estrogen receptor modulator. Mol Endocrinol. 2008 Jan;22(1):65–77.

Published In

Mol Endocrinol

DOI

ISSN

0888-8809

Publication Date

January 2008

Volume

22

Issue

1

Start / End Page

65 / 77

Location

United States

Related Subject Headings

  • Transcription, Genetic
  • Sequence Homology, Amino Acid
  • Selective Estrogen Receptor Modulators
  • Reverse Transcriptase Polymerase Chain Reaction
  • Receptors, Estrogen
  • Promoter Regions, Genetic
  • Molecular Structure
  • Molecular Sequence Data
  • Hydroxycholesterols
  • Humans