Research IndicatorsGraph generated 06 August 2015 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 06 August, 2015 using data from PubMed, MeSH and CancerIndex
Specific Cancers (1)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
Search the Epigenomics database and view relevant gene tracks of samples.
Latest Publications: HSD11B1 (cancer-related)
Celestino AT, Levy D, Maria Ruiz JL, Bydlowski SPABCB1, ABCC1, and LRP gene expressions are altered by LDL, HDL, and serum deprivation in a human doxorubicin-resistant uterine sarcoma cell line.
Biochem Biophys Res Commun. 2015; 457(4):664-8 [PubMed
] Related Publications
Multidrug resistance (MDR) is the major cause of cancer treatment failure. The ATP-binding cassette-B1 (ABCB1) transporter, also known as MDR1 or P-glycoprotein, is thought to promote the efflux of drugs from cells. MDR is also associated with the multidrug resistance-associated protein 1 (ABCC1) and the lung resistance-related protein (LRP), a human major vault protein. Moreover, MDR has a complex relationship with lipids. The ABCB1 has been reported to modulate cellular cholesterol homeostasis. Conversely, cholesterol has been reported to modulate multidrug transporters. However, results reported to date are contradictory and confusing. The aim of this study was to investigate whether LDL, HDL, and serum deprivation could influence ABCB1, ABCC1, and LRP expression in a human doxorubicin-resistant uterine sarcoma cell line. ABCB1 and ABCC1 expression increased after 24 h of serum deprivation, and expression returned to basal levels after 72 h. LDL, depending on concentration, increased ABCB1, ABCC1, and LRP expression. ABCB1 expression increased at low HDL, and decreased at high HDL concentrations. We demonstrated that serum deprivation and lipoproteins, particularly LDL, modulated ABCB1 expression and, to a lesser extent, ABCC1 expression. This finding may link the phenomena of drug transport, cholesterol metabolism and cancer.
The paraoxonase (PON) gene family consists of three members, PON1, PON2 and PON3. All PON proteins possess antioxidant properties and lipo-lactonase activities, and are implicated in the pathogenesis of several inflammatory diseases including atherosclerosis, Alzheimer's, Parkinson's, diabetes and cancer. Despite the role of PON proteins in critical cellular functions and associated pathologies, the physiological substrates and molecular mechanisms by which PON proteins function as anti-inflammatory proteins remain largely unknown. PON1 is found exclusively extracellular and associated solely with high-density lipoprotein (HDL) particles in the circulation, and, in part, confers the anti-oxidant and anti-inflammatory properties associated with HDL. Recent studies demonstrated that the intracellular PON proteins; PON2 and PON3 (i) are associated with mitochondria and mitochondria-associated membranes, (ii) modulate mitochondria-dependent superoxide production, and (iii) prevent apoptosis. Overexpression of PON2 and PON3 genes protected (i) mitochondria from antimycin or oligomycin mediated mitochondrial dysfunction and (ii) ER stress and ER stress mediated mitochondrial dysfunction. These studies illustrate that the anti-inflammatory effects of PON2 and PON3 may, in part, be mediated by their role in mitochondrial and associated organelle function. Since oxidative stress as a result of mitochondrial dysfunction is implicated in the development of inflammatory diseases including atherosclerosis and cancer, these recent studies on PON2 and PON3 proteins may provide a mechanism for the scores of epidemiological studies that show a link between PON genes and numerous inflammatory diseases. Understanding such mechanisms will provide novel routes of intervention in the treatment of diseases associated with pro-inflammatory oxidative stress.
Raju K, Punnayanapalya SS, Mariyappa N, et al.Significance of the plasma lipid profile in cases of carcinoma of cervix: a tertiary hospital based study.
Asian Pac J Cancer Prev. 2014; 15(8):3779-84 [PubMed
] Related Publications
AIMS: To study alterations of plasma lipid profiles in carcinoma cervix and to assess significance compared with controls in different histological grades and stages.
MATERIALS AND METHODS: Totals of 99 histopathologically diagnosed cases and 35 controls from a tertiary hospital situated in the southern part of India which caters the rural and semi-urban populations were considered for the study. Fasting blood samples were taken to analyze total cholesterol (TC), triglycerides (TG), high density lipoprotein cholesterol (HDL-C) and low density lipoproteins cholesterol (LDL-C), for comparison of cases, grouped according to histological grades and stages, and controls. One way ANOVA was used for multiple group comparisons and the Student's t test (unpaired) for group wise comparisons. For all tests a 'p' value of 0.05 or less was considered as significant.
RESULTS: Out of 99 cases, most (n-39) were seen in the 40-49 year age group followed by 60-69 years (n-22). Serum TG significantly differed between cases and controls but without any relation to differentiation grade. The lipid profile parameters in various grades of cervical cancer were not statistically significant. Statistically significant increase of TC and LDL-C values was observed with increase in stage of the disease.
CONCLUSIONS: The study showed TG is elevated in cervical cancer, and that TC and LDL-C are proportional to the spread of cancer as it increases from stage I to stage IV. An in-depth study of molecular changes in lipid metabolism in cervical cancer patients, enzymes/ genes responsible and alterations in LDL receptors is necessary to provide information to decide whether the lipid profile has any diagnostic/prognostic role in cervical cancer.
Thymiakou E, Kardassis DNovel mechanism of transcriptional repression of the human ATP binding cassette transporter A1 gene in hepatic cells by the winged helix/forkhead box transcription factor A2.
Biochim Biophys Acta. 2014; 1839(6):526-36 [PubMed
] Related Publications
ATP binding cassette transporter A1 (ABCA1) plays a key role in the biogenesis of HDL by promoting the efflux of cellular cholesterol and phospholipids to lipid free apoA-I. Mutations in the ABCA1 gene cause Tangier disease which is characterized by near or complete absence of circulating plasma HDL. In the present study we show that the winged helix/forkhead box containing transcription factor A2 (FOXA2) shown previously to play a role in glucose and bile acid homeostasis in the liver and in energy utilization in adipose tissue is a negative modulator of ABCA1 gene expression in hepatic cells. We show that the ABCA1 promoter contains three FOXA2 binding elements in the proximal region. Two of the sites are localized in a region of the ABCA1 promoter enriched in binding elements for transcriptional repressor proteins whereas the third site is the core of the TATA element of the ABCA1 promoter. Inhibition of FOXA2 binding to the ABCA1 promoter by site-directed mutagenesis or FOXA2 gene expression by siRNA was associated with increased ABCA1 promoter activity and protein levels. Overexpression of FOXA2 inhibited both the constitutive ABCA1 gene expression as well as ABCA1 gene induction by oxysterols and retinoids via nuclear receptors LXRα/RXRα. In summary, the present study identifies transcription factor FOXA2 as a negative modulator of ABCA1 gene expression in hepatic cells and reveals a novel mechanism of transcriptional repression by FOXA2 which involves the TATA element of the ABCA1 gene.
BACKGROUND: Epidemiological and clinical studies suggest comorbidity between prostate cancer (PCA) and cardiovascular disease (CVD) risk factors. However, the relationship between these two phenotypes is still not well understood. Here we sought to identify shared genetic loci between PCA and CVD risk factors.
METHODS: We applied a genetic epidemiology method based on conjunction false discovery rate (FDR) that combines summary statistics from different genome-wide association studies (GWAS), and allows identification of genetic overlap between two phenotypes. We evaluated summary statistics from large, multi-centre GWA studies of PCA (n=50 000) and CVD risk factors (n=200 000) [triglycerides (TG), low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol, systolic blood pressure, body mass index, waist-hip ratio and type 2 diabetes (T2D)]. Enrichment of single nucleotide polymorphisms (SNPs) associated with PCA and CVD risk factors was assessed with conditional quantile-quantile plots and the Anderson-Darling test. Moreover, we pinpointed shared loci using conjunction FDR.
RESULTS: We found the strongest enrichment of P-values in PCA was conditional on LDL and conditional on TG. In contrast, we found only weak enrichment conditional on HDL or conditional on the other traits investigated. Conjunction FDR identified altogether 17 loci; 10 loci were associated with PCA and LDL, 3 loci were associated with PCA and TG and additionally 4 loci were associated with PCA, LDL and TG jointly (conjunction FDR <0.01). For T2D, we detected one locus adjacent to HNF1B.
CONCLUSIONS: We found polygenic overlap between PCA predisposition and blood lipids, in particular LDL and TG, and identified 17 pleiotropic gene loci between PCA and LDL, and PCA and TG, respectively. These findings provide novel pathobiological insights and may have implications for trials using targeting lipid-lowering agents in a prevention or cancer setting.
PURPOSE OF REVIEW: Several mutations in the apoB, proprotein convertase subtilisin/kexin type 9 (PCSK9), and MTP genes result in low or absent levels of apoB and LDL-cholesterol in plasma, which cause familial hypobetalipoproteinemia and abetalipoproteinemia. Mutations in the ANGPTL3 gene cause familial combined hypolipidemia. Clinical manifestations range from none to severe, debilitating, and life-threatening disorders. This review summarizes recent genetic, metabolic, and clinical findings and presents an update on management strategies.
RECENT FINDINGS: Cases of cirrhosis and hepatocellular carcinoma have now been identified in heterozygous familial hypobetalipoproteinemia probably because of decreased triglyceride transport capacity from the liver. ANGPTL3 mutations cause low levels of LDL-cholesterol and low HDL-cholesterol in compound heterozygotes and homozygous individuals, decrease reverse cholesterol transport, and lower glucose levels. The effect on atherosclerosis is unknown; however, severe fatty liver has been identified. Loss-of-function mutations in PCSK9 cause familial hypobetalipoproteinemia, which appears to lower risk for coronary artery disease and has no adverse sequelae. Phase III clinical trials are now underway examining the effect of PCSK9 inhibitors on cardiovascular events in combination with statin drugs.
SUMMARY: Mutations causing low LDL-cholesterol and apoB have provided insight into lipid metabolism, disease associations, and the basis for drug development to lower LDL-cholesterol in disorders causing high levels of cholesterol. Early diagnosis and treatment are necessary to prevent adverse sequelae from familial hypobetalipoproteinemia and abetalipoproteinemia.
OBJECTIVES: We aimed to investigate whether glucocorticoid receptor gene polymorphisms are associated with clinical and metabolic profiles in patients with polycystic ovary syndrome. Polycystic ovary syndrome is a complex endocrine disease that affects 5-8% of women and may be associated with metabolic syndrome, which is a risk factor for cardiovascular disease. Cortisol action and dysregulation account for metabolic syndrome development in the general population. As glucocorticoid receptor gene (NR3C1) polymorphisms regulate cortisol sensitivity, we hypothesized that variants of this gene may be involved in the adverse metabolic profiles of patients with polycystic ovary syndrome.
METHOD: Clinical, metabolic and hormonal profiles were evaluated in 97 patients with polycystic ovary syndrome who were diagnosed according to the Rotterdam criteria. The alleles of the glucocorticoid gene were genotyped. Association analyses were performed using the appropriate statistical tests.
RESULTS: Obesity and metabolic syndrome were observed in 42.3% and 26.8% of patients, respectively. Body mass index was positively correlated with blood pressure, triglyceride, LDL-c, total cholesterol, glucose and insulin levels as well as HOMA-IR values and inversely correlated with HDL-c and SHBG levels. The BclI and A3669G variants were found in 24.7% and 13.4% of alleles, respectively. BclI carriers presented a lower frequency of insulin resistance compared with wild-type subjects.
CONCLUSION: The BclI variant is associated with a lower frequency of insulin resistance in women with polycystic ovary syndrome. Glucocorticoid gene polymorphism screening during treatment of the syndrome may be useful for identifying subgroups of at-risk patients who would benefit the most from personalized treatment.
Zhang W, Wei D, Sun X, et al.Family-based analysis of adiponectin gene polymorphisms in Chinese Han polycystic ovary syndrome.
Fertil Steril. 2014; 101(5):1419-23 [PubMed
] Related Publications
OBJECTIVE: To study the association between two single-nucleotide polymorphisms (SNPs) variants (rs2241766 and rs1501299) of the adiponectin gene (ADIPOQ) and polycystic ovary syndrome (PCOS) in PCOS family trios.
DESIGN: Family-based study.
SETTING: University hospital.
PATIENT(S): A total of 224 unrelated PCOS probands, their biologic parents, and 204 control subjects.
INTERVENTION(S): Anthropometric, hormonal, and metabolic assessment; genotype detection.
MAIN OUTCOME MEASURE(S): Basic endocrine, serum fasting glucose (FG), fasting insulin (FINS), total cholesterol (TC), triglycerides (TG), and low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels were measured. The transmission disequilibrium test (TDT) was used to analyze the association between two SNPs of ADIPOQ and PCOS.
RESULT(S): A significant positive association was detected between SNP rs1501299 and PCOS. Compared with AA genotype, AC and CC genotypes had increased risk for PCOS, and the difference remained significant after adjustment for age, body mass index, and testosterone (T). The levels of T, TG, HDL cholesterol, and FINS were significantly higher in obese PCOS patients. However, we failed to find significant overtransmission of the other SNP, rs2241766, from parents to PCOS offspring. The genotype frequencies of rs2241766 and rs1501299 were not different in obese and lean PCOS patients and their parents.
CONCLUSION(S): TDT confirms that SNP rs1501299 in the ADIPOQ is significantly associated with the risk of PCOS in the Chinese Han population. The present data may provide a basis for further studies of the role of the ADIPOQ in the etiology of PCOS.
Lipids and cholesterol in particular, have long been associated with breast cancer (BC) onset and progression. However, the causative effects of elevated lipid levels and breast cancer remain largely undisclosed and were the subject of the present study.We took advantage of well-established in vitro and in vivo models of cholesterol enrichment to exploit the mechanism involved in LDL-cholesterol favouring BC growth and invasiveness. We analyzed its effects in models that mimic different BC subtypes and stages.Our data show that LDL-cholesterol (but not HDL-cholesterol) promotes BC cells proliferation, migration and loss of adhesion, hallmarks of the epithelial to mesenchymal transition. In vivo studies modeling cholesterol levels showed that breast tumors are consistently larger and more proliferative in hypercholesterolemic mice, which also have more frequently lung metastases. Microarray analysis revealed an over expression of intermediates of Akt and ERK pathways suggesting a survival response induced by LDL, confirmed by WB analyses. Gene expression analysis also evidenced an activation of ErbB2 signaling pathway and decreased expression of adhesion molecules (cadherin-related family member3, CD226, Claudin 7 and Ocludin) in the cells exposed to LDL.Together, the present work shows novel mechanistic evidence that high LDL-cholesterol levels promote BC progression. These data provide rationale for the clinical control of cholesterol levels in BC patients.
CONTEXT: Although inflammation is clearly associated with obesity, diabetes, and insulin resistance, the role of chronic inflammation in the etiology of polycystic ovary syndrome (PCOS) is unclear.
OBJECTIVE: To determine whether chronic inflammation plays a causal role in the etiology of PCOS, we tested for an association between PCOS and genetic markers mapping to 80 members of the inflammatory pathway.
DESIGN: This was a case-control association study.
SETTING: The setting was an academic medical center.
PATIENTS OR PARTICIPANTS: A total of 905 index case patients with PCOS and 955 control women (108 intensively phenotyped subjects with normal androgen levels and regular menses and 847 minimally phenotyped subjects with regular menses and no history of PCOS).
INTERVENTIONS: Subjects were genotyped at single nucleotide polymorphisms mapping to 80 inflammatory genes. Logistic regression was used to test for an association between 822 single nucleotide polymorphisms and PCOS after adjustment for population stratification, body mass index, and/or age. In the index patients, we also tested for association with 11 quantitative traits (body mass index and testosterone, fasting insulin, fasting glucose, 2-hour postchallenge glucose, LH, FSH, total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglyceride levels).
MAIN OUTCOME MEASURES: The evidence for an association with PCOS and with 11 quantitative traits was investigated.
RESULTS: Nominally significant evidence for an association was observed with MAP3K7, IKBKG, TNFRS11A, AKT2, IL6R, and IRF1, but no results remained statistically significant after adjustment for multiple testing.
CONCLUSIONS: Genetic variation in the inflammatory pathway is not a major contributor to the etiology of PCOS or related quantitative traits in women with PCOS.
Ahmadi B, Nikzamir A, Ghafari SM, et al.Lack of association between cyclooxygenase 2-765G/C gene polymorphism and breast cancer risk in Ahvaz, west-south Iran.
Mol Biol Rep. 2014; 41(2):997-1001 [PubMed
] Related Publications
Cyclooxygenases are key enzymes in conversion of arachidonic acid into prostaglandin H2. Cyclooxygenase-2 (COX-2) increases prostaglandins in neoplastic tissue. COX-2 has important roles in cell proliferation cancers, angiogenesis, and alzheimer. COX-2 is up-regulated in several types of cancer, and it is hypothesized that COX-2 expression may be genetically influenced. Our main objective was to evaluated the association of polymorphism COX-2 with risk of breast cancer in khouzestan province, and the second objective of the study was to evaluate the association with biochemistry parameters. This study consisting of 150 patients with breast cancer and 120 normal DNA was extracted from the white blood cells. Polymorphism cox2 gene was detected by polymerase chain reaction according to the standard methods. The profile lipids and estrogen were measured in two groups by standard methods. Chi square analysis showed that there was no association between breast cancer risk and COX-2 -765G>C genotype and alleles. Also, no association were observed between -765G>C polymorphism and biochemistry parameters. A multiple logistic regression model with cox2 genotypes and LDL and HDL as covariates revealed that there is no significant association between cox2 genotypes and risk of breast cancer, but higher values of LDL and HDL significantly increase risk of breast cancer.
Lam UD, Lerchbaum E, Schweighofer N, et al.Association of MEP1A gene variants with insulin metabolism in central European women with polycystic ovary syndrome.
Gene. 2014; 537(2):245-52 [PubMed
] Related Publications
Polycystic ovary syndrome (PCOS) shows not only hyperandrogenemia, hirsutism and fertility problems, but also metabolic disturbances including obesity, cardiovascular events and type-2 diabetes. Accumulating evidence suggests some degree of inflammation associated with prominent aspects of PCOS. We aimed to investigate the association of genetic variants 3'UTR rs17468190 (G/T) of the inflammation-associated gene MEP1A (GenBank ID: NM_005588.2) with metabolic disturbances in PCOS and healthy control women. Genetic variants rs17468190 (G/T) of MEP1A gene were analyzed in 576 PCOS women and 206 controls by using the Taqman fluorogenic 5'-exonuclease assay. This polymorphism was tested for association with anthropometric, metabolic, hormonal, and functional parameters of PCOS. There was a borderline significant difference in genotype distribution between PCOS and control women (p=0.046). In overweight/obese PCOS patients, the variants rs17468190 (G/T) in the MEP1A gene are associated with glucose and insulin metabolism. In a dominant model, the GG genotype of the MEP1A gene was more strongly associated with insulin metabolism in overweight/obese PCOS women (body mass index, BMI>25 kg/m(2)), than in GT+TT genotypes. The MEP1A GG-carriers showed a significantly increased homeostatic model assessment - insulin resistance (HOMA-IR) (p=0.003), elevation of fasting insulin (p=0.004) and stimulated insulin (30 min, p<0.001; 60 min, p=0.009; 120 min, p=0.009) as well as triglyceride (p=0.032) levels. MEP1A is a possible target gene for disease modification in PCOS. It might contribute to the abnormalities of glucose metabolism and insulin sensitivity and serve as a diagnostic or therapeutic target gene for PCOS.
Kopp JBJC viruria and kidney disease in APOL1 risk genotype individuals: is this a clue to a gene × environment interaction?
Kidney Int. 2013; 84(6):1069-72 [PubMed
] Related Publications
APOL1 nephropathy occurs in a minority of genetically at-risk individuals, suggesting that other factors, such as other genes or environmental factors, contribute. Divers and colleagues report that among individuals with two APOL1 risk alleles, those with JC viruria are less likely to manifest kidney disease compared with those lacking JC viruria. These data might suggest that JC virus infection confers protection against glomerular injury, perhaps by altering cell function or generating immunity against a related polyomavirus.
Fang BA, Kovačević Ž, Park KC, et al.Molecular functions of the iron-regulated metastasis suppressor, NDRG1, and its potential as a molecular target for cancer therapy.
Biochim Biophys Acta. 2014; 1845(1):1-19 [PubMed
] Related Publications
N-myc down-regulated gene 1 (NDRG1) is a known metastasis suppressor in multiple cancers, being also involved in embryogenesis and development, cell growth and differentiation, lipid biosynthesis and myelination, stress responses and immunity. In addition to its primary role as a metastasis suppressor, NDRG1 can also influence other stages of carcinogenesis, namely angiogenesis and primary tumour growth. NDRG1 is regulated by multiple effectors in normal and neoplastic cells, including N-myc, histone acetylation, hypoxia, cellular iron levels and intracellular calcium. Further, studies have found that NDRG1 is up-regulated in neoplastic cells after treatment with novel iron chelators, which are a promising therapy for effective cancer management. Although the pathways by which NDRG1 exerts its functions in cancers have been documented, the relationship between the molecular structure of this protein and its functions remains unclear. In fact, recent studies suggest that, in certain cancers, NDRG1 is post-translationally modified, possibly by the activity of endogenous trypsins, leading to a subsequent alteration in its metastasis suppressor activity. This review describes the role of this important metastasis suppressor and discusses interesting unresolved issues regarding this protein.
Kim HJ, Moon JH, Kim HM, et al.The hypolipidemic effect of cilostazol can be mediated by regulation of hepatic low-density lipoprotein receptor-related protein 1 (LRP1) expression.
Metabolism. 2014; 63(1):112-9 [PubMed
] Related Publications
OBJECTIVES: Cilostazol, a selective phosphodiesterase 3 (PDE3) inhibitor, is a vasodilator and an anti-thrombotic agent. The mechanism whereby cilostazol reduces plasma triglyceride is not completely understood. Here we investigated the effect of cilostazol on a remnant lipoprotein receptor, low-density lipoprotein receptor-related protein 1 (LRP1), which has been reported to play an essential role in clearance of circulating triglyceride in the liver.
MATERIALS/METHODS: Total cellular expression, and functional and transcriptional regulation of LRP1 were analyzed in human hepatocarcinoma cell lines incubated with cilostazol. Also, C57BL/6 mice were subjected to high-fat diet (60% kcal) and cilostazol (30 mg/kg) treatment for 10 weeks.
RESULTS: Cilostazol increased both mRNA and protein expression of LRP1 in HepG2 and Hep3B cells. In addition, enhanced transcriptional activity of the LRP1 promoter containing a peroxisome proliferator response element (PPRE) was observed after cilostazol exposure. Cilostazol treatment enhanced the uptake of lipidated apoE3, and this effect was abolished when LRP1 was silenced by siRNA knockdown. High-fat diet induced hyperglycemia with high level of plasma triglycerides, and reduced hepatic LRP1 expression in mice. Treatment with cilostazol for the same period of time, however, successfully prevented this down-regulation of LRP1 expression and reduced plasma triglycerides.
CONCLUSION: Taken together, our results demonstrated that cilostazol enhances LRP1 expression in liver by activating PPARγ through the PPRE in the LRP1 promoter. Increased hepatic LRP1 may be essential for the reduction of circulating triglycerides brought about by cilostazol.
Wang J, Gao Y, Wang L, et al.A variant (rs932335) in the HSD11B1 gene is associated with colorectal cancer in a Chinese population.
Eur J Cancer Prev. 2013; 22(6):523-8 [PubMed
] Related Publications
Glucocorticoid hormones have been reported to contribute to the regulation of cellular proliferation and differentiation and to inhibit the growth of cells in several colon tumors and adenocarcinoma cell lines. As a regulator of glucocorticoid levels, type I isoform HSD11B1 is a bidirectional enzyme but acts predominantly as an oxidoreductase to yield active glucocorticoids, cortisol or corticosterone. To date, studies investigating the associations between the polymorphisms of HSD11B1 and the risk for cancer have shown inconclusive results. In our study, we aimed to investigate whether the polymorphisms of HSD11B1 may influence the genetic susceptibility to colorectal cancer (CRC) in a Chinese population. Four single-nucleotide polymorphisms of HSD11B1 (rs846910 G/A, rs11807619 G/T, rs932335 C/G, and rs13306421 G/A) were detected using a PCR-ligase detection reaction in a case-control study comprising 110 CRC patients and 118 controls. Logistic regression was used to evaluate genetic associations with the occurrence of CRC. Real-time PCR was used to test the mRNA expression of HSD11B1 in 18 CRC tissues. The frequencies of the rs932335 GC genotype were significantly higher among the patients compared with controls (P=0.019). Compared with individuals carrying the GG genotype, individuals with the GC/CC genotype had a significantly increased susceptibility to CRC occurrence (odds ratio=2.23, 95% confidence interval=1.27-3.94, P=0.008). In cancer tissues, patients carrying the GG genotype also displayed an increased mRNA level of HSD11B1 (P=0.019). These results suggested that the HSD11B1 rs932335 G/C polymorphism had an effect on CRC occurrence. These findings also suggest that the functional polymorphism rs932335 in intron4 of HSD11B1 may influence the susceptibility to and progression of CRC in a Chinese population. Large population-based prospective studies are required to validate our findings.
Danilo C, Gutierrez-Pajares JL, Mainieri MA, et al.Scavenger receptor class B type I regulates cellular cholesterol metabolism and cell signaling associated with breast cancer development.
Breast Cancer Res. 2013; 15(5):R87 [PubMed
] Free Access to Full Article Related Publications
INTRODUCTION: Previous studies have identified cholesterol as an important regulator of breast cancer development. High-density lipoprotein (HDL) and its cellular receptor, the scavenger receptor class B type I (SR-BI) have both been implicated in the regulation of cellular cholesterol homeostasis, but their functions in cancer remain to be established.
METHODS: In the present study, we have examined the role of HDL and SR-BI in the regulation of cellular signaling pathways in breast cancer cell lines and in the development of tumor in a mouse xenograft model.
RESULTS: Our data show that HDL is capable of stimulating migration and can activate signal transduction pathways in the two human breast cancer cell lines, MDA-MB-231 and MCF7. Furthermore, we also show that knockdown of the HDL receptor, SR-BI, attenuates HDL-induced activation of the phosphatidylinositol 3-kinase (PI3K)/protein Kinase B (Akt) pathway in both cell lines. Additional investigations show that inhibition of the PI3K pathway, but not that of the mitogen-activated protein kinase (MAPK) pathway, could lead to a reduction in cellular proliferation in the absence of SR-BI. Importantly, whereas the knockdown of SR-BI led to decreased proliferation and migration in vitro, it also led to a significant reduction in tumor growth in vivo. Most important, we also show that pharmacological inhibition of SR-BI can attenuate signaling and lead to decreased cellular proliferation in vitro. Taken together, our data indicate that both cholesteryl ester entry via HDL-SR-BI and Akt signaling play an essential role in the regulation of cellular proliferation and migration, and, eventually, tumor growth.
CONCLUSIONS: These results identify SR-BI as a potential target for the treatment of breast cancer.
Li S, Tao T, Wang L, et al.The expression of 11β-HSDs, GR, and H6PDH in subcutaneous adipose tissue from polycystic ovary syndrome subjects.
Horm Metab Res. 2013; 45(11):802-7 [PubMed
] Related Publications
The aim of the work was to investigate the expression of 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 and 2, hexose-6-phosphate dehydrogenase (H6PDH), and glucocorticoids receptor (GR) mRNA in subcutaneous adipose tissue (SAT) from obese women with or without polycystic ovary syndrome (PCOS), and the association between their expression and the adipocytokines' concentration. Sixteen women with PCOS (group P) and 18 age- and BMI-matched control women (group C) were enrolled for the study. Subcutaneous adipose tissue was collected from the abdomen. The genes' expression was detected by real-time PCR, and the adipocytokines' concentration was measured by ELISA. Peripheral insulin sensitivity was assessed by homeostatic assessment model of insulin resistance (HOMA-IR). β-cell function was assessed by homeostasis model assessment of β-cell function (HOMA-IS). The expression of 11β-HSD1 mRNA was significantly higher in PCOS subjects (p<0.05) than controls; there was no difference for the expression of 11β-HSD2, GR, and H6PDH mRNA between the 2 groups. The stepwise multiple linear regression analysis showed that the mRNA level of 11β-HSD1 was positively correlated to the concentration of the serum tumor necrosis factor-alpha (TNF-α). Expression of 11β-HSD1 mRNA was increased in the SAT from the women with PCOS, which may contribute to the increased local active glucocorticoids (cortisol), and subsequently affects the secretion of the local adipose tissue.
Lecke SB, Morsch D, Spritzer PMCirculating levels and subcutaneous adipose tissue gene expression of pigment epithelium-derived factor in polycystic ovary syndrome and normal women: a case control study.
Reprod Biol Endocrinol. 2013; 11:77 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Polycystic ovary syndrome (PCOS) has been recognized as a metabolic disorder, manifested by abdominal obesity, insulin resistance, dyslipidemia and hypertension. Pigment epithelium-derived factor (PEDF), a member of the serine protease inhibitor family, is a pleiotropic protein known for its antiangiogenic, antioxidant, and neuroprotective properties and has been shown to induce insulin resistance and play a role in glucose metabolism. Recent studies investigating circulating PEDF levels show elevated serum PEDF in association with insulin resistance in normal-weight women with PCOS, but not in obese PCOS patients. The aims of this study were 1) to assess PEDF gene expression in subcutaneous adipose tissue (scAT) from women with PCOS and nonhirsute, ovulatory controls, and 2) to determine the circulating levels of PEDF in these groups.
METHODS: Total RNA was extracted from adipose tissue biopsy samples and reverse-transcribed to cDNA. Real-time quantitative PCR was performed to determine relative gene expression levels.
RESULTS: The 22 women with PCOS and 14 non-PCOS controls included in the study had similar age, BMI, and fasting glucose, triglycerides, and HDL-cholesterol levels. Participants with PCOS exhibited higher 2 h oral glucose tolerance test levels (p = 0.006), total (p = 0.026) and LDL-cholesterol (p = 0.036), Ferriman-Gallwey score (p = 0.003) and total testosterone (p = 0.001) as compared to controls. BMI-adjusted PEDF serum levels and scAT gene expression were similar in the PCOS and control groups (p = 0.622 and p = 0.509, respectively). Circulating PEDF levels were not associated with scAT PEDF gene expression. Multiple regression analysis revealed that, in women with PCOS, insulin contributed positively and significantly to serum PEDF (p = 0.027), independently of testosterone.
CONCLUSION: Serum PEDF levels and scAT gene expression were associated with metabolic risk factors, but did not differ between women with PCOS and age- and BMI-matched controls. Circulating levels and scAT gene expression of PEDF were not associated in the study subjects, suggesting additional sources for PEDF in addition to or instead of fat tissue.
Ramos RB, Wiltgen D, Spritzer PMPolymorphisms of TCF7L2 gene in South Brazilian women with polycystic ovary syndrome: a cross-sectional study.
Eur J Endocrinol. 2013; 169(5):569-76 [PubMed
] Related Publications
OBJECTIVE: To assess whether TCF7L2 single nucleotide polymorphisms rs7903146 C/T and rs11196236 C/T are associated with polycystic ovary syndrome (PCOS) in South Brazilian women.
DESIGN: Cross-sectional study.
METHODS: Two hundred PCOS patients and 102 non-hirsute, ovulatory controls were genotyped by real-time PCR. Haplotypes were constructed from the combination of both polymorphisms. Frequencies were inferred using the PHASE 2.1.1 software.
RESULTS AND CONCLUSIONS: The distribution of rs7903146 (PCOS, 54.4% CC; 28.5% CT; 17.1% TT; controls, 51.0% CC; 37.0% CT; 12.0% TT) and rs11196236 (PCOS, 4.3% CC; 33.5% CT; 62.2% TT; controls, 3.2% CC; 35.5% CT; 61.3% TT) was similar between the groups. rs7903146 and rs11196236 were not in linkage disequilibrium (|D'|=0.34; r(2)=0.07). PCOS participants were younger, with higher age-adjusted BMI, waist circumference, blood pressure, triglycerides, insulin, homeostasis model assessment index to estimate insulin resistance and total testosterone, and lower HDL-C and sex hormone binding globulin vs controls. In PCOS, no differences between genotypes and haplotypes were found for clinical and metabolic variables. However, for each T (rs7903146) and T (rs11196236) allele added to the haplotypes, a variation of 5.87 cm in waist (P trend=0.01), 10.7 mg/dl in total cholesterol (P trend=0.03), and 10.3 mg/dl in LDL-C (P trend=0.01) was recorded. TCF7L2 variants are probably not implicated in PCOS development in South Brazilian women.
Gaibar M, Fernández G, Romero-Lorca A, et al.Tamoxifen therapy in breast cancer: do apolipoprotein E genotype and menopausal state affect plasma lipid changes induced by the drug?
Int J Biol Markers. 2013 Oct-Dec; 28(4):e371-6 [PubMed
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OBJECTIVE: This study examines the lipid profile change produced in response to tamoxifen (TAM) treatment, and its possible relationship with both apolipoprotein E genotype and menopausal state in patients with breast cancer.
METHODS: Blood samples were collected from 86 Spanish women with breast cancer before initiating TAM treatment and in the following 6, 12 and 18 months of treatment. Plasma lipid levels (total cholesterol, triglycerides, HDL-cholesterol and LDL-cholesterol) were determined using an automatic analyzer. Genotypes for apolipoprotein E (ApoE) were identified by PCR-RFLP using the HhaI enzyme.
RESULTS: In all patients, significant reductions in total cholesterol and LDL-cholesterol concentrations and a significant increase in triglyceride concentrations were observed after 6, 12, and 18 months of TAM treatment compared to baseline (p<0.01 for each time point). In the subset of APOE4-negative patients, triglyceride concentrations also significantly increased after 6, 12, and 18 months of treatment (p=0.019, p=0.045, p=0.001, respectively), while APOE4-positive patients showed no significant lipid changes at 12 and 18 months. However, after 18 months of TAM treatment the overall triglyceride concentrations had risen by 24.75% in APOE4-negative patients vs 29.9% in APOE4-positive patients. In postmenopausal women, significant reductions in total cholesterol, LDL-cholesterol and LDL/HDL ratios were observed at each time point (p<0.020 for each).
CONCLUSIONS: TAM treatment induced similar plasma triglyceride increases in patients with positive or negative APOE genotype. Compared to premenopausal patients, postmenopausal breast cancer patients showed a more beneficial lipid profile change in response to treatment.
Eroglu M, Yilmaz N, Yalcinkaya S, et al.Enhanced HDL-cholesterol-associated anti-oxidant PON-1 activity in prostate cancer patients.
Kaohsiung J Med Sci. 2013; 29(7):368-73 [PubMed
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Increases in the generation of reactive oxygen species and decreases in antioxidant enzyme activities with aging have been reported in the prostate, and are also observed in age-related disorders such as atherosclerosis, Alzheimer's disease, and cataracts. Several studies have demonstrated that proteins are targets for reactive oxidants in cells, and that oxidized proteins accumulate during aging, oxidative stress and in some pathological conditions. However, only a limited number of studies have actually evaluated oxidative damage in relation to HDL-cholesterol-associated antioxidant enzyme activities or have assessed its relationship with prostate cancer. In this study, we examined the effect of HDL-cholesterol-associated antioxidant enzyme activities, paraoxonase1, arylesterase and new oxidative stress parameters (total oxidant status, total antioxidant status [and oxidative stress index]) in newly-diagnosed prostate cancer patients and healthy controls. There were no significant differences in oxidative stress parameters and lipid parameters between prostate cancer patients and controls, however, paraoxonase1 enzyme activity, and non-HDL-cholesterol levels were higher in prostate cancer patients than controls. The results of this study were derived from a small number of subjects, but might represent an important working hypothesis for further research in a larger number of cases to clarify the role of paraoxonase1 overproduction on the prostate and its clinical relevance.
Liu HW, Zhang F, Fan P, et al.Effects of apolipoprotein E genotypes on metabolic profile and oxidative stress in southwest Chinese women with polycystic ovary syndrome.
Eur J Obstet Gynecol Reprod Biol. 2013; 170(1):146-51 [PubMed
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OBJECTIVE: Apolipoprotein (APO) E genetic polymorphism plays an important role in lipid and lipoprotein metabolism, and has been shown to be associated with the risk of metabolic and cardio-cerebrovascular diseases and late-onset Alzheimer's disease. It is not clear, however, whether there are any relationships between the APOE genotypes and PCOS in Chinese women. The aim of this study was to investigate the relationship between APOE genotypes and the risk of polycystic ovary syndrome (PCOS) and to evaluate the effects of the genotypes on metabolic profile and oxidative stress in south-west Chinese women.
STUDY DESIGN: A total of 625 patients with PCOS based on the Rotterdam consensus criteria and 514 control women from a population of Chinese Han nationality in the Chengdu area were studied during 2006-2012. APOE genotypes were determined by PCR and restriction fragment length polymorphism analysis. Clinical and metabolic parameters, serum malondialdehyde concentration, and total antioxidant capacity were analyzed.
RESULTS: No significant differences were found in the frequencies of APOE genotypes (E2/2, E2/3, E2/4, E3/3, E3/4, E4/4) and alleles (ε2, ε3, ε4) between PCOS and control groups. Compared with ε3 homozygotes (APOE3/3), however, ε2 carriers (APOE2/2+APOE2/3+APOE2/4) had significantly higher body mass index, waist circumference and waist-to-hip ratio, a more adverse glucose and insulin metabolic profile, lower high density lipoprotein (HDL)-cholesterol (C) and APOA1 levels, higher triglyceride (TG)/HDL-C ratio and prevalence of metabolic syndrome (MS), whereas ε4 carriers (APOE3/4+APOE4/4) had higher total cholesterol (TC) and low density lipoprotein (LDL)-C levels in patients with PCOS.
CONCLUSIONS: In a cohort of south-west Chinese women, there were no significant associations between any APOE genotype and PCOS. The APOE ε2 allele seems to be related to abdominal obesity, insulin resistance and MS in PCOS women.
BACKGROUND: Cardiovascular-related toxicities have been reported among survivors of osteosarcoma.
METHODS: Fasting blood samples from 24 osteosarcoma survivors were analyzed for high-sensitivity C-reactive protein (hsCRP), triglycerides, total cholesterol, high-density lipoprotein (HDL), apolipoprotein-ß, lipoprotein (a), fibrinogen, circulating endothelial cells (CECs), and surface expression of vascular cell adhesion molecule-1 (VCAM-1). Values were compared to subjects in the natural history Coronary Artery Risk Development in Young Adults (CARDIA) cohort study except for CECs and VCAM-1 expression, which were compared to controls studied at the University of Minnesota Lillehei clinical trials unit.
PROCEDURE: Survivors (54.2% male), median age 18 years (9-32) at diagnosis, 36.5 years (20-56) at evaluation were treated with a variety of chemotherapeutic exposures, all but one were exposed to doxorubicin (median dose 450 mg/m(2) ; range: 90-645 mg/m(2)), 14 (58.3%) received cisplatin, and 3 (12.5%) were exposed to carboplatin. Two survivors (8.3%) received radiation therapy for disease relapse. Compared to CARDIA subjects, mean hsCRP (3.0 mg/L ± 2.0 vs. 1.6 ± 2.3), triglycerides (151 mg/dl ± 81.7 vs. 95.4 ± 101.3), lipoprotein (a) (34.9 mg/dl ± 17.7 vs. 13.8 ± 22.0), and fibrinogen (315.0 mg/dl ± 49.3 vs. 252.4 ± 61.7) were significantly elevated. The number of CECs (0.47 cells/ml ± 2.5 vs. 0.92 ± 2.5) did not differ while surface expression of VCAM-1 (86.4% ± 34.0 vs. 42.1 ± 33.8) was significantly elevated compared to controls.
CONCLUSIONS: Among survivors of osteosarcoma, assessed a median of 14 years from diagnosis, there is evidence of vascular inflammation, dyslipidemia, and early atherogenesis.
Individuals with HIV infection and two apolipoprotein L1 gene (APOL1) risk variants frequently develop nephropathy. Here we tested whether non-HIV viral infections influence nephropathy risk via interactions with APOL1 by assessing APOL1 genotypes and presence of urine JC and BK polyoma virus and plasma HHV6 and CMV by quantitative polymerase chain reaction. We analyzed 300 samples from unrelated and related first-degree relatives of African Americans with nondiabetic nephropathy using linear and nonlinear mixed models to account for familial relationships. The four groups evaluated were APOL1 zero/one versus two risk alleles, with or without nephropathy. Urine JCV and BKV were detected in 90 and 29 patients, respectively, whereas HHV6 and CMV were rare. Adjusting for family age at nephropathy, gender, and ancestry, presence of JCV genomic DNA in urine and APOL1 risk alleles were significantly negatively associated with elevated serum cystatin C, albuminuria (albumin-to-creatinine ratio over 30 mg/g), and kidney disease defined as an eGFR under 60 ml/min per 1.73 m(2) and/or albuminuria in an additive (APOL1 plus JCV) model. BK viruria was not associated with kidney disease. Thus, African Americans at increased risk for APOL1-associated nephropathy (two APOL1 risk variants) with JC viruria had a lower prevalence of kidney disease, suggesting that JCV interaction with APOL1 genotype may influence kidney disease risk.
Apolipoprotein A-I (Apo A-I) is a major component of high density lipoproteins (HDL) that transport cholesterol in circulation. We have constructed an expression plasmid encoding a chimeric molecule encompassing interleukin-15 (IL-15) and Apo A-I (pApo-hIL15) that was tested by hydrodynamic injections into mice and was co-administered with a plasmid encoding the sushi domain of IL-15Rα (pSushi) in order to enhance IL-15 trans-presentation and thereby bioactivity. The pharmacokinetics of the Apo A-I chimeric protein were much longer than non-stabilized IL-15 and its bioactivity was enhanced in combination with IL-15Rα Sushi. Importantly, the APO-IL-15 fusion protein was incorporated in part into circulating HDL. Liver gene transfer of these constructs increased NK and memory-phenotype CD8 lymphocyte numbers in peripheral blood, spleen and liver as a result of proliferation documented by CFSE dilution and BrdU incorporation. Moreover, the gene transfer procedure partly rescued the NK and memory T-cell deficiency observed in IL-15Rα(-/-) mice. pApo-hIL15+ pSushi gene transfer to the liver showed a modest therapeutic activity against subcutaneously transplanted MC38 colon carcinoma tumors, that was more evident when tumors were set up as liver metastases. The improved pharmacokinetic profile and the strong biological activity of APO-IL-15 fusion protein holds promise for further development in combination with other immunotherapies.
Fenkci SM, Fenkci V, Oztekin O, Rota SSerum calcitonin gene-related peptide levels in women with polycystic ovary syndrome.
Arch Gynecol Obstet. 2013; 287(6):1235-9 [PubMed
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PURPOSE: Calcitonin gene-related peptide (CGRP) is an amino acid neuropeptide with widespread expression. It has potent effects on lipid and energy metabolism. It induces insulin resistance. This study was planned to determine CGRP levels in women with polycystic ovary syndrome (PCOS).
METHODS: Forty-seven women with PCOS and 34 healthy controls were evaluated in this controlled clinical study. Serum lipid sub-fractions, postprandial and fasting glucose, insulin and other hormones (gonadotropins, androgens) and CGRP levels were measured. Homeostasis model assessment (HOMA-IR) was used to estimate insulin resistance.
RESULTS: Waist measurements, postprandial and fasting glucose and fasting insulin levels and free androgen index and HOMA-IR were significantly higher in subjects with PCOS. However, the women with PCOS had considerably lower high-density lipoprotein cholesterol levels than healthy subjects. Serum CGRP levels were higher in study subjects than in controls, although it was statistically insignificant.
CONCLUSIONS: Serum CGRP level was not related with insulin resistance, ovarian hyperandrogenism and dyslipidemia in abdominally obese women with PCOS. These outcomes propose that CGRP may not play a pivotal role in the pathogenesis of PCOS.
Ding Y, Wang W, Feng M, et al.A biomimetic nanovector-mediated targeted cholesterol-conjugated siRNA delivery for tumor gene therapy.
Biomaterials. 2012; 33(34):8893-905 [PubMed
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RNA interference holds tremendous potential as a therapeutic approach of malignant tumors. However, safe and efficient nanovectors are extremely lack for systemic delivery of small interfering RNA (siRNA). The study aimed to develop a biomimetic nanovector, reconstituted high density lipoprotein (rHDL), mediating targeted cholesterol-conjugated siRNA (Chol-siRNA) delivery for Pokemon gene silencing therapy. Chol-siRNA-loaded rHDL nanoparticles (rHDL/Chol-siRNA complexes) were prepared using thin-film dispersion method and their characteristics were investigated in detail. RHDL/Chol-siRNA complexes at the optimal volume ratio (lipid: Chol-siRNA) exhibited high Chol-siRNA-loading efficiency (~99%), desirable nanoparticle size and excellent stability in serum. In addition, by analyzing Chol-siRNA release profile, rHDL/Chol-siRNA complexes displayed sustained-release characteristic and storage stability. Observations from FACS and confocal microscopic analyses revealed that rHDL-mediated carboxyfluorescein tagged Chol-siRNA (FAM-Chol-siRNA) transfection resulted in highly efficient uptake and specific cytoplasmic delivery of FAM-Chol-siRNA into human hepatocellular carcinoma cell line HepG2 via HDL-receptor mediated mechanism. In vitro cytotoxicity, apoptosis and Western-blot analyses revealed significant cellular growth inhibition and decrease of Pokemon and Bcl-2 protein expression in HepG2 cells treated with Chol-siRNA-Pokemon-loaded rHDL nanoparticles (rHDL/Chol-siRNA-Pokemon complexes), respectively. In in vivo studies, the near-infrared (NIR) dye Cy5 labeled Chol-siRNA-loaded rHDL nanoparticles (rHDL/Cy5-Chol-siRNA complexes) obviously accumulated in tumor of nude mice after i.v. administration as compared with Cy5-Chol-siRNA-loaded lipoplexes (Lipos/Cy5-Chol-siRNA complexes). Morover, rHDL/Chol-siRNA-Pokemon complexes demonstrated great tumor growth inhibition and significant decrease of Pokemon and Bcl-2 protein expression in vivo. These results suggested that rHDL should be an ideal non-viral tumor-targeting vector for Chol-siRNA transfer, and rHDL-mediated Chol-siRNA-Pokemon delivery might be a promising new strategy for gene therapy in hepatocellular carcinoma.
Many drugs have decreased therapeutic activity due to issues with absorption, distribution, metabolism and excretion. The co-formulation or covalent attachment of drugs with fatty acids has demonstrated some capacity to overcome these issues by improving intestinal permeability, slowing clearance and binding serum proteins for selective tissue uptake and metabolism. For orally administered drugs, albeit at low level of availability, the presence of fatty acids and triglycerides in the intestinal lumen may promote intestinal uptake of small hydrophilic molecules. Small lipophilic drugs or acylated hydrophilic drugs also show increased lymphatic uptake and enhanced passive diffusional uptake. Fatty acid conjugation of small and large proteins or peptides has exhibited protracted plasma half-lives, site-specific delivery and sustained release upon parenteral administration. These improvements are most likely due to associations with lipid-binding serum proteins, namely albumin, LDL and HDL. These molecular interactions, although not fully characterized, could provide the ability of using the endogenous carrier systems for improving therapeutic outcomes.
El Roz A, Bard JM, Huvelin JM, Nazih HLXR agonists and ABCG1-dependent cholesterol efflux in MCF-7 breast cancer cells: relation to proliferation and apoptosis.
Anticancer Res. 2012; 32(7):3007-13 [PubMed
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BACKGROUND: Liver X receptor (LXR) plays a key role in reverse cholesterol transport by inducing the expression of the ATP-binding cassette (ABC) transporters, implicated in cholesterol efflux. Recent data showed that LXR agonists inhibit the proliferation of multiple types of human cancer cells. However, whether these effects are related to cholesterol efflux has not yet been elucidated.
MATERIALS AND METHODS: Effects of two LXR agonists (TO901317 and 22(R)-hydroxycholesterol [22(R)-HC]) on proliferation, apoptosis and cholesterol efflux were examined in MCF-7 breast cancer cells.
RESULTS: Treatment with LXR agonists (TO901317 at 20 μM and 22(R)-HC at 2 μg/ml) inhibited proliferation and induced apoptosis of MCF-7 cells. Furthermore, LXR activation resulted in an increase in gene and protein levels of ABCG1 transporters and in cholesterol efflux to isolated high-density lipoprotein (HDL), without affecting the ABCA1/APOA-I mediated efflux. Under these conditions, a remarkable reduction of intracellular and membrane-associated cholesterol levels was observed.
CONCLUSION: LXR activation in MCF-7 cells could deprive cells of cholesterol, required for their growth, by stimulating its efflux, resulting in the inhibition of cell proliferation and in stimulation of apoptosis.