27-hydroxysterol binds ESR1, ESR2

Stable Identifier
Reaction [binding]
Homo sapiens
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27-hydroxycholesterol binds directly to ESR1 and ESR2 to modulate estrogen signaling in a cell-, tissue-, and gene-specific manner, making it a physiological selective ER modulator (SERM) (Umetani et al, 2007; Nelson et al, 2013; Nguyen et al, 2015). In the context of breast cancer, 27-HC acts as an estrogen agonist, promoting ER-dependent cellular proliferation. The development of resistance to aromatase inhibitors in breast cancer can arise in part through epigenetic reprogramming that activates the cholesterol biosynthetic pathway, elevating 27-HC levels and resulting in constitutive ER alpha activation (Nelson et al, 2013; Nguyen et al, 2015). Note that 27-HC binding to the estrogen receptors likely occurs in the context of a chaperone complex as is the case for estrogens, however this has not been explicitly demonstrated.
Literature References
PubMed ID Title Journal Year
17873880 27-Hydroxycholesterol is an endogenous SERM that inhibits the cardiovascular effects of estrogen

Gormley, AK, Cummins, CL, Mangelsdorf, DJ, Yuhanna, IS, Umetani, M, Korach, KS, Domoto, H, Javitt, NB, Shaul, PW

Nat. Med. 2007
26610607 Differential epigenetic reprogramming in response to specific endocrine therapies promotes cholesterol biosynthesis and cellular invasion

Darbre, P, Patel, N, Steel, JH, Magnani, L, Woodley, L, Meira, A, Győrffy, B, Coombes, RC, Minucci, S, Nguyen, VT, Lombardo, Y, Vircillo, V, Frige, G, Patten, DK, Periyasamy, M, Ali, S, Castellano, L, Barozzi, I, Faronato, M

Nat Commun 2015
24288332 27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology

Sullivan, PM, Jasper, JS, Howe, MK, Geradts, J, Pillai, RV, Sondhi, V, Wardell, SE, Carver, NJ, Nelson, ER, Park, S, McDonnell, DP, Suchindran, S, Umetani, M

Science 2013
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