scholarly journals RORγ is a targetable master regulator of cholesterol biosynthesis in a cancer subtype

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Demin Cai ◽  
Junjian Wang ◽  
Bei Gao ◽  
Jin Li ◽  
Feng Wu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Regression ◽  
Cholesterol Biosynthesis ◽  
Cholesterol Content ◽  
Cholesterol Homeostasis ◽  
Synthesis Rate ◽  
Master Regulator ◽  
Cancer Subtype ◽  
Estrogen Receptor Positive ◽  
Chromatin Acetylation

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.

scholarly journals SUN-751 RORγ Is a Master Regulator of Tumor Lipid Metabolism

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Hong-Wu Chen
Keyword(s):  
Cholesterol Metabolism ◽  
Cholesterol Biosynthesis ◽  
Cholesterol Homeostasis ◽  
Synthesis Rate ◽  
Host Animal ◽  
Master Regulator ◽  
Genome Wide ◽  
Histone H3k27 ◽  
Lowering Drug ◽  
Potent Tumor

Abstract Lipid and cholesterol metabolism reprogramming is strongly linked to tumorigenesis and therapeutic resistance. Our recent genetic disruptions via CRISPR KO and gene silencing and pharmacological inhibition clearly demonstrated that nuclear receptor RORγ plays a crucial role in control of lipid and cholesterol biosynthesis gene programs specifically in certain types and subtypes of cancer cells and tumors. Indeed, its antagonists display potent tumor inhibitions in patient-derived xenografts (PDX) and in immune-intact tumor models. Interestingly, RORγ inhibition resulted in decreased cholesterol synthesis rate specifically in tumors without significant impact to the host animal cholesterol homeostasis. Our ChIP-seq demonstrated that in a subtype of breast cancer RORγ cistrome is largely overlapping with that of SREBP2, a well-established master regulator of lipid and cholesterol biosynthesis. Our further analyses found that RORγ functions dominantly over that of SREBP2 via its association with SREBP2 and facilitation of its genome-wide recruitment and histone H3K27 acetylation. Inhibition of RORγ completely negates the negative feedback activation of the cholesterol program induced by cholesterol-lowering drug statins and mediated by SREBP2. Treatment of animals with the antagonists in combination with statins showed a highly synergistic anti-tumor effects. Together, our study uncovers RORγ as a novel master regulator of lipid and cholesterol metabolism operating selectively in subtypes of cancer.

scholarly journals Genomic agonism and phenotypic antagonism between estrogen and progesterone receptors in breast cancer

2016 ◽  
Vol 2 (6) ◽  
pp. e1501924 ◽  
Author(s):  
Hari Singhal ◽  
Marianne E. Greene ◽  
Gerard Tarulli ◽  
Allison L. Zarnke ◽  
Ryan J. Bourgo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Target Genes ◽  
Tumor Regression ◽  
Progesterone Receptors ◽  
Estrogen Signaling ◽  
Breast Cancers ◽  
Estrogen Action ◽  
Cellular Processes ◽  
Estrogen Receptor Positive ◽  
Estrogen Antagonist

The functional role of progesterone receptor (PR) and its impact on estrogen signaling in breast cancer remain controversial. In primary ER+ (estrogen receptor–positive)/PR+ human tumors, we report that PR reprograms estrogen signaling as a genomic agonist and a phenotypic antagonist. In isolation, estrogen and progestin act as genomic agonists by regulating the expression of common target genes in similar directions, but at different levels. Similarly, in isolation, progestin is also a weak phenotypic agonist of estrogen action. However, in the presence of both hormones, progestin behaves as a phenotypic estrogen antagonist. PR remodels nucleosomes to noncompetitively redirect ER genomic binding to distal enhancers enriched for BRCA1 binding motifs and sites that link PR and ER/PR complexes. When both hormones are present, progestin modulates estrogen action, such that responsive transcriptomes, cellular processes, and ER/PR recruitment to genomic sites correlate with those observed with PR alone, but not ER alone. Despite this overall correlation, the transcriptome patterns modulated by dual treatment are sufficiently different from individual treatments, such that antagonism of oncogenic processes is both predicted and observed. Combination therapies using the selective PR modulator/antagonist (SPRM) CDB4124 in combination with tamoxifen elicited 70% cytotoxic tumor regression of T47D tumor xenografts, whereas individual therapies inhibited tumor growth without net regression. Our findings demonstrate that PR redirects ER chromatin binding to antagonize estrogen signaling and that SPRMs can potentiate responses to antiestrogens, suggesting that cotargeting of ER and PR in ER+/PR+ breast cancers should be explored.

Mechanisms of Tumor Regression and Resistance to Estrogen Deprivation and Fulvestrant in a Model of Estrogen Receptor–Positive, HER-2/neu-Positive Breast Cancer

2006 ◽  
Vol 66 (16) ◽  
pp. 8266-8273 ◽  
Author(s):  
Suleiman Massarweh ◽  
C. Kent Osborne ◽  
Shou Jiang ◽  
Alan E. Wakeling ◽  
Mothaffar Rimawi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Tumor Regression ◽  
Estrogen Deprivation ◽  
Estrogen Receptor Positive ◽  
Her 2 ◽  
Positive Breast Cancer

scholarly journals Establishment of a normal-derived estrogen receptor-positive cell line comparable to the prevailing human breast cancer subtype

Oncotarget ◽  
2017 ◽  
Vol 8 (6) ◽  
pp. 10580-10593 ◽  
Author(s):  
Branden M. Hopkinson ◽  
Marie C. Klitgaard ◽  
Ole William Petersen ◽  
René Villadsen ◽  
Lone Rønnov-Jessen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cell Line ◽  
Human Breast Cancer ◽  
Breast Cancer Subtype ◽  
Human Breast ◽  
Cancer Subtype ◽  
Estrogen Receptor Positive

The Effect of Oxidized Cholesterol on the Aorta of Rabbits- Scanning Electron Microscopic Observations

1982 ◽  
Vol 40 ◽  
pp. 340-341
Author(s):  
S. K. Pena ◽  
C. B. Taylor ◽  
J. Hill ◽  
J. Safarik
Keyword(s):  
Cholesterol Biosynthesis ◽  
Cholesterol Content ◽  
Arterial Injury ◽  
Electron Microscopic ◽  
Aortic Smooth Muscle ◽  
Oxidized Cholesterol ◽  
Initial Event ◽  
Membrane Structure And Function ◽  
Scanning Electron Microscopic ◽  
And Function

Introduction: Oxidized cholesterol derivatives have been demonstrated in various cell cultures to be very potent inhibitors of 3-hvdroxy-3- methylglutaryl Coenzyme A reductase which is a principle regulator of cholesterol biosynthesis in the cell. The cholesterol content in the cells exposed to oxidized cholesterol was found to be markedly decreased. In aortic smooth muscle cells, the potency of this effect was closely related to the cytotoxicity of each derivative. Furthermore, due to the similarity of their molecular structure to that of cholesterol, these oxidized cholesterol derivatives might insert themselves into the cell membrane, alter membrane structure and function and eventually cause cell death. Arterial injury has been shown to be the initial event of atherosclerosis.

Sign in / Sign up

Export Citation Format

Share Document