Abstract：
:Tumor subtype-specific metabolic reprogrammers could serve as targets of therapeutic intervention. Here we show that triple-negative breast cancer (TNBC) exhibits a hyper-activated cholesterol-biosynthesis program that is strongly linked to nuclear receptor RORγ, compared to estrogen receptor-positive breast cancer. Genetic and pharmacological inhibition of RORγ reduces tumor cholesterol content and synthesis rate while preserving host cholesterol homeostasis. We demonstrate that RORγ functions as an essential activator of the entire cholesterol-biosynthesis program, dominating SREBP2 via its binding to cholesterol-biosynthesis genes and its facilitation of the recruitment of SREBP2. RORγ inhibition disrupts its association with SREBP2 and reduces chromatin acetylation at cholesterol-biosynthesis gene loci. RORγ antagonists cause tumor regression in patient-derived xenografts and immune-intact models. Their combination with cholesterol-lowering statins elicits superior anti-tumor synergy selectively in TNBC. Together, our study uncovers a master regulator of the cholesterol-biosynthesis program and an attractive target for TNBC.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Cai D,Wang J,Gao B,Li J,Wu F,Zou JX,Xu J,Jiang Y,Zou H,Huang Z,Borowsky AD,Bold RJ,Lara PN,Li JJ,Chen X,Lam KS,To KF,Kung HJ,Fiehn O,Zhao R,Evans RM,Chen HWdoi
10.1038/s41467-019-12529-3subject
Has Abstractpub_date
2019-10-11 00:00:00pages
4621issue
1issn
2041-1723pii
10.1038/s41467-019-12529-3journal_volume
10pub_type
杂志文章abstract：:Inner hair cells (IHCs) are the primary receptors for hearing. They are housed in the cochlea and convey sound information to the brain via synapses with the auditory nerve. IHCs have been thought to be electrically and metabolically independent from each other. We report that, upon developmental maturation, in mice 3...
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pub_type： 杂志文章
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