Oxysterols, oxidized derivatives of cholesterol, have been implicated in multiple pathologies, including cancer. In breast cancer, the link is especially strong due to interactions between oxysterols and estrogen receptor activity. Here, we provide the first dedicated study of 113 oxysterol-related genes in breast cancer patients of the luminal subtype, in terms of both their somatic and germline variability, using targeted high-throughput DNA sequencing of 100 normal-tumor pairs with very high coverage. In the full cohort, or subsets of patients stratified by therapy, we found 12 germline variants in ABCA1, ABCA8, ABCC1, GPR183, LDLR, MBTPS1, NR1I2, OSBPL2, OSBPL3, and OSBPL5 to associate with poor survival of patients and variants in ABCA8, ABCG2, and HSD3B7 (three in total) associated with better survival. However, no associations remained significant after correction for multiple tests. Analysis of somatic variants revealed significantly (after FDR correction) poorer survival in patients mutated in CYP46A1 and 9 interacting (according to STRING analysis) genes, as well as in OSBPL3 and a set of 20 genes that collectively associated with the progesterone receptor status of patients. We propose further exploration of these genes in an integrative manner together with gene expression and epigenomic data.
Oxysteroly jsou oxidované deriváty cholesterolu, které mají pleiotropní účinky. V tomto článku se zaměříme zejména na funkci oxysterolů v organismu, která je dána vazbou na velké množství receptorů, jimiž jsou oxysteroly ligandy, a dále pak na roli oxysterolů u vybraných lidských onemocnění. Oxysteroly se podílejí na udržování homeostázy cholesterolu, a to zejména vazbou na LXR či SREBPs, čímž se spouští kaskáda dějů podílejících se na regulaci metabolismu cholesterolu. Pomocí modulace estrogenových receptorů a Hedgehog signalizace ovlivňují morfogenezi, reprodukci, imunitní reakce a zánětlivou odpověď. V článku je dále uveden vztah oxysterolů a jednotlivých typů nádorů, zejména karcinomu prsu, prostaty, kolorektálního karcinomu a plicního karcinomu. Popisována je také účast oxysterolů v patogenezi aterosklerózy a Alzheimerovy choroby.
Oxysterols are oxidized cholesterol derivatives that have pleiotropic effects. We will focus on the function of oxysterols in the body, because oxysterols are ligands of various receptors. Thus, we will try to explain the role of oxysterols in selected human diseases. Oxysterols have several functions in the body: they are involved in maintaining cholesterol homeostasis, especially by binding to LXR or SREBPs triggering a cascade of events involved in the regulation of cholesterol metabolism. By modulating estrogen receptors and Hedgehog signaling, they affect morphogenesis, reproduction, immune response, and inflammatory response. Furthermore, the relationship between oxysterols and individual tumour types, in particular breast, prostate, colorectal and lung cancer, is discussed. The involvement of oxysterols in the pathogenesis of atherosclerosis and Alzheimer's disease is also described.
- Klíčová slova
- LXR,
- MeSH
- Alzheimerova nemoc patologie MeSH
- arterioskleróza patologie MeSH
- karcinogeneze patologie MeSH
- lidé MeSH
- oxysteroly * metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
- MeSH
- ateroskleróza prevence a kontrola MeSH
- jaterní receptor X MeSH
- kardiovaskulární nemoci prevence a kontrola MeSH
- lidé MeSH
- metabolický syndrom * diagnóza etiologie farmakoterapie komplikace MeSH
- oxidační stres MeSH
- oxysteroly * chemie metabolismus škodlivé účinky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
Oxysterols, oxygenated derivatives of cholesterol, are formed in the human body or ingested. Experimental evidence suggests that due to their diverse functions, e.g. modulating the activity of receptors such as liver X receptors, oxysterol-binding and metabolizing proteins, and several ATP binding cassette transporters, oxysterols may contribute to a number of human disorders including cancer. Genetic variability of oxysterol pathways represents another side of this process, affecting carcinogenesis and cancer progression. This review summarizes information about both the physiological role of oxysterol pathway genes and observed associations between their genetic variability and cancer incidence, progression, and therapy outcome. Besides candidate gene studies, results of genome-wide association studies are presented as well. The survey of available data shows some potential genetic biomarkers that, if clinically validated, may allow the stratification of individuals into genetically defined groups for prediction of individual cancer risk and subsequent screening strategies for early diagnosis.
- MeSH
- časná detekce nádoru MeSH
- lidé MeSH
- nádorové biomarkery metabolismus MeSH
- nádory diagnóza genetika metabolismus MeSH
- oxysteroly metabolismus MeSH
- signální transdukce * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
OBJECTIVE: This study investigated whether gene expression levels of key modulators of the oxysterol signalling pathway modify the prognosis of patients with oestrogen receptor-positive (ER+) breast carcinomas via interaction with endocrine therapy. CONTEXT: The prognosis of patients with ER+ breast carcinoma depends on several factors. Previous studies have suggested that some oxygenated forms of cholesterol (oxysterols) bind to oestrogen receptor and anti-oestrogen binding site which may deregulate cholesterol homoeostasis and influence effect of therapy. DESIGN: The expression levels of 70 oxysterol pathway genes were evaluated in a test set of breast carcinomas differing in ER expression. The genes differentially expressed in ER+ tumours were assessed in a comprehensive set of ER+ tumours to evaluate their clinical significance. PATIENTS: A total of 193 primary patients with breast carcinoma were included. MEASUREMENTS: The transcript levels were determined by quantitative real-time polymerase chain reaction. RESULTS: The expression levels of 23 genes were found to be specifically dysregulated in ER+ tumours compared to ER- tumours of the test set. The expression levels of ABCG2, CYP7B1, CYP24A1, CYP39A1 and CH25H genes were found to be strongly associated with disease stage; however, none of the gene expression levels were associated with disease-free survival in patients treated with endocrine therapy. CONCLUSIONS: The expression of a number of oxysterol pathway genes is significantly modulated by ER expression and associated with the clinical stage of patients. However, the expression of oxysterol pathway genes was not found to modify the prognosis of ER+ patients with breast carcinoma treated with endocrine therapy.
- MeSH
- biosyntetické dráhy genetika MeSH
- cholesterol farmakologie MeSH
- endokrinní systém MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory prsu diagnóza genetika metabolismus MeSH
- oxysteroly metabolismus MeSH
- přežití po terapii bez příznaků nemoci MeSH
- prognóza MeSH
- receptory pro estrogeny analýza MeSH
- regulace genové exprese u nádorů * MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
The main biological cause of oxysterols is the oxidation of cholesterol. They differ from cholesterol by the presence of additional polar groups that are typically hydroxyl, keto, hydroperoxy, epoxy, or carboxyl moieties. Under typical conditions, oxysterol concentration is maintained at a very low and precisely regulated level, with an excess of cholesterol. Like cholesterol, many oxysterols are hydrophobic and hence confined to cell membranes. However, small chemical differences between the sterols can significantly affect how they interact with other membrane components, and this in turn can have a substantial effect on membrane properties. In this spirit, this review describes the biological importance and the roles of oxysterols in the human body. We focus primarily on the effect of oxysterols on lipid membranes, but we also consider other issues such as enzymatic and nonenzymatic synthesis processes of oxysterols as well as pathological conditions induced by oxysterols.
- MeSH
- cholesterol metabolismus MeSH
- lidé MeSH
- lipidové dvojvrstvy metabolismus MeSH
- nemoc MeSH
- oxidace-redukce MeSH
- oxysteroly metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
