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.

Origin and diversification of steroids: Co-evolution of enzymes and nuclear receptors

“…The binding of many xenobiotics and natural products to the ER is consistent with recent evidence that the vertebrate ER has conformational flexibility, which allows it to bind diverse ligands, including 27-hydroxycholesterol [58][59] [ Figure 5], trifluoromethyl-phenylvinyl-E2 [60], as well as tamoxifen and diethylstilbestrol. Thus, there may have been several classes of ligands, including sterols, xenobiotics and natural chemicals that were the original ligand(s) for the ancestral ER.…”

Insights from the structure of estrogen receptor into the evolution of estrogens: Implications for endocrine disruption

“…Recently, Umetani et al [40] reported that several hydroxylated cholesterols including 27-hydroxycholesterol [27-OH-C], 22R-OH-C, 24S-OH-C and 25-OH-C bound human ER and human ER . 27-OH-C was the most potent, and in some mammalian cells 27-OH-C functions as a partial agonist for human ER and ER [40][41][42][43]. The Kd of 27-OH-C for ER and ER is about 1.3 M and 0.4 M, respectively [40][41][42], which is over 10 3 times higher than the Kd of E2 for human ER and ER [30,40].…”

“…27-OH-C was the most potent, and in some mammalian cells 27-OH-C functions as a partial agonist for human ER and ER [40][41][42][43]. The Kd of 27-OH-C for ER and ER is about 1.3 M and 0.4 M, respectively [40][41][42], which is over 10 3 times higher than the Kd of E2 for human ER and ER [30,40]. Nevertheless, a Kd of 1 M is physiologically relevant because the circulating concentration of 27-OH-C is from 0.15 to 0.73 M, [40][41][42].…”

“…His-524 on ER does not contact the 27-hydroxyl, which may explain the substantially the lower affinity of 27-OH-C for ER and ER [40][41][42].…”

Proliferation of human mammary cancer cells exposed to 27-hydroxycholesterol

“…Serum and the fluids bathing cells, organs and tissues contain compounds with the potential to imitate estrogens. in this regard, it has been reported that 27-hydroxycholesterol (27Ohc), an oxysterol produced by the intramitochondrial oxidation of cholesterol, may act as a non-conventional SmEr in estradiol-target cells (10,11). in normal subjects, plasma 27Ohc concentration is in the same order of magnitude as the dissociation constant of the complex between Er and 27Ohc, thus assuring their stable association.…”