Reactome | 27-hydroxysterol binds ESR1, ESR2

27-hydroxysterol binds ESR1, ESR2

Stable Identifier

R-HSA-9038029

Type

Reaction [binding]

Species

Homo sapiens

Compartment

nucleoplasm

ReviewStatus

5/5

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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