@article{fd45dfae9ca842cb8b3d739c0bea7f9a,
title = "RORγ 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 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.",
author = "Demin Cai and Junjian Wang and Bei Gao and Jin Li and Feng Wu and Zou, {June X.} and Jianzhen Xu and Yuqian Jiang and Hongye Zou and Zenghong Huang and Borowsky, {Alexander D.} and Bold, {Richard J.} and Lara, {Primo N.} and Li, {Jian Jian} and Xinbin Chen and Lam, {Kit S.} and To, {Ka Fai} and Kung, {Hsing Jien} and Oliver Fiehn and Ruqian Zhao and Evans, {Ronald M.} and Chen, {Hong Wu}",
note = "Funding Information: We thank Dr. Peter Tontonoz for his valuable discussion and inputs. We thank Drs. Joan Massague and Haifa Shen for their kind gift of MB231-LM2 and 4T1 tumor cells, respectively. We also thank members of the Genomics Shared Resources of UC Davis Cancer Center for their technical help and Christopher Chen for his help in editing. This work was supported in part by grants from the NIH (R01CA224900 and R01CA206222 to H-W.C.). The UCDCCC Genomics Shared Resource is funded by the UC Davis Comprehensive Cancer Center Support Grant (CCSG) awarded by the National Cancer Institute (NCI P30CA093373). Publisher Copyright: {\textcopyright} 2019, The Author(s).",
year = "2019",
month = dec,
day = "1",
doi = "10.1038/s41467-019-12529-3",
language = "English",
volume = "10",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}
