27-Hydroxycholesterol Is an Endogenous Selective Estrogen Receptor Modulator
Open Access
- 1 January 2008
- journal article
- other
- Published by The Endocrine Society in Molecular Endocrinology
- Vol. 22 (1), 65-77
- https://doi.org/10.1210/me.2007-0383
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 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 ERα 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.Keywords
This publication has 56 references indexed in Scilit:
- What do we know about the mechanisms of aromatase inhibitor resistance?The Journal of Steroid Biochemistry and Molecular Biology, 2006
- Serum High-Density Lipoprotein Cholesterol, Metabolic Profile, and Breast Cancer RiskJNCI Journal of the National Cancer Institute, 2004
- Profiling of Estrogen Up- and Down-Regulated Gene Expression in Human Breast Cancer Cells: Insights into Gene Networks and Pathways Underlying Estrogenic Control of Proliferation and Cell PhenotypeEndocrinology, 2003
- Estrogen receptor α and Sp1 regulate progesterone receptor gene expressionMolecular and Cellular Endocrinology, 2003
- Estrogen Receptor-α Mediates the Protective Effects of Estrogen Against Vascular InjuryCirculation Research, 2002
- Hormones and Hormone Antagonists: Mechanisms of Action in Carcinogenesis of Endometrial and Breast CancerHormone and Metabolic Research, 2001
- Molecular determinants of nuclear receptor-corepressor interactionJournal of Bone and Joint Surgery, 1999
- Differential Ligand Activation of Estrogen Receptors ERα and ERβ at AP1 SitesScience, 1997
- Cloning of a novel receptor expressed in rat prostate and ovary.Proceedings of the National Academy of Sciences of the United States of America, 1996
- Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-ANature, 1986