ROR? is a targetable master regulator of cholesterol biosynthesis in a cancer subtype.

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 ROR?, compared to estrogen receptor-positive breast cancer. Genetic and pharmacological inhibition of ROR? reduces tumor cholesterol content and synthesis rate while preserving host cholesterol homeostasis. We demonstrate that ROR? 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. ROR? inhibition disrupts its association with SREBP2 and reduces chromatin acetylation at cholesterol-biosynthesis gene loci. ROR? 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.

SUBMITTER: Cai D 

PROVIDER: S-EPMC6789042 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature