Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Axillary lymph node involvement in breast cancer is a marker of recurrence risk. Despite aggressive adjuvant therapy, recurrence in patients with four or more involved lymph nodes approaches 50% at 5 years from diagnosis. Markers that can distinguish those likely to relapse from those likely to be cured are needed to tailor therapy and provide accurate prognostic information to patients. Although most work in this area has focused on tumor characteristics, we hypothesized that the host environment might also play a role in determining risk of relapse. We hypothesized that host inflammatory response, mediated in part by production of interleukin-6 (IL-6), might play a role in the elimination of microscopic residual tumor. Polymorphisms in the IL-6 promoter region appear to modulate serum levels of the cytokine via regulation of gene transcription. A single nucleotide polymorphism involving substitution of cytosine for guanine at position -174 has been associated with reduced transcription and improved outcome in a variety of nonmalignant diseases, including coronary artery disease and several autoimmune conditions. Tumor necrosis factor (TNF) alpha is a proinflammatory cytokine that also plays a role in regulating IL-6 transcription. We hypothesized that polymorphisms in IL-6 (-174 G>C) or TNF-alpha (G-238 or G-308) might be associated with prognosis in a subset of patients with high-risk breast cancer. Genotyping was performed on DNA from stored stem cells in 80 breast cancer patients diagnosed with at least four positive axillary lymph nodes at diagnosis who underwent anthracycline-based adjuvant chemotherapy followed by high-dose multiagent chemotherapy with stem cell rescue. Cox proportional hazards models were used to estimate the effect of genotype and other known prognostic factors on disease-free and overall survival (DFS and OS, respectively). The presence of at least one C allele in the IL-6 promoter at position -174 was significantly associated with both DFS and OS compared with G/G homozygotes. After adjustment for estrogen receptor (ER) status, number of involved lymph nodes, and tumor size, those patients carrying the G/G genotype had a 2.1-fold increase in the rate of failure and a 2.6-fold increase in the rate of death compared with carriers of any C allele at a mean follow-up of 55 months. ER status modulated the effect of IL-6 polymorphism: both DFS and OS were most favorable in patients who were carriers of any C-allele (G/C or C/C) and had ER-positive tumors. The presence of either G/G genotype or an ER-negative tumor increased the hazard of failure [hazard ratio (HR), 2.6 and 3.2, respectively] and death (HR, 2.0 and 2.2, respectively). The combination of both G/G genotype and ER-negative tumor resulted in an additional increase in the hazard of failure (HR, 5.4; four-group comparison, P = 0.003) and death (HR, 6.2; four-group comparison, P = 0.001). TNF-alpha -308 and -238 polymorphisms were not associated with variation in DFS or OS in this cohort. The IL-6-174 promoter polymorphism is associated with clinical outcome in this cohort of node-positive breast cancer patients who received high-dose adjuvant therapy. IL-6 genotype modulated the effect of ER status on outcome. These results support the hypothesis that IL-6 may play an important role in the control of micrometastatic disease in breast cancer. Additional studies are needed to confirm these results and elucidate the mechanisms responsible for these differences.
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PMID:Interleukin-6 -174G-->C polymorphism is associated with improved outcome in high-risk breast cancer. 1463 38

Two new single nucleotide mutations were observed within the promoter region of human interleukin-6 gene (IL-6) in the tumour sample of a patient with sporadic breast cancer, which was a somatic change. Both mutations, one at -125 (C > G) and the other at position -173 (G > T) from the translation start site, were transversions observed at new positions, not reported earlier. In addition to these two novel mutations in this patient, a known somatic polymorphism was also observed at position -174 (G > C) (from the transcription initiation site, redesignated as -236 from the translational initiation site as per the HUGO nomenclature). Further, a preliminary comparative analysis of the studied promoter region by the 'ConsInspector 3.0' program, where the mutated sequence (AF362378) was compared with the sequence existing in the database (Y00081), depicted the presence of the variations in putative binding sites for transcription factors such as glucocorticoid response element (GRE) and nuclear factor kappa-B (NFkappa-B), which could lead to differential expression of this gene.
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PMID:Two novel somatic mutations in the human interleukin 6 promoter region in a patient with sporadic breast cancer. 1467 92

Serum and tissue levels of interleukin-6 (IL-6) have been implicated in the biological phenotype of breast carcinoma. A common G/C polymorphism at position -174 of the IL-6 promoter can influence the expression level of this gene. We therefore investigated for associations between this polymorphism and various phenotypic features in a series of 256 breast cancers. Individuals who were homozygous for the C allele (n=55) were more likely to have higher-grade tumours (P=0.039) with ductal histology (P=0.030) compared to those harbouring at least one wild-type G allele (n=201). Homozygosity for the C allele was also associated with significantly worse overall survival (P=0.031). We conclude that the -174 C allele of IL-6 is associated with a more aggressive breast cancer phenotype.
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PMID:The -174 G/C gene polymorphism in interleukin-6 is associated with an aggressive breast cancer phenotype. 1473 87

The adipocytokines are biologically active polypeptides that are produced either exclusively or substantially by the adipocytes, and act by endocrine, paracrine, and autocrine mechanisms. Most have been associated with obesity, hyperinsulinaemia, type 2 diabetes, and chronic vascular disease; in addition, six adipocytokines--vascular endothelial growth factor, hepatocyte growth factor, leptin, tumour necrosis factor-alpha, heparin-binding epidermal growth factor-like growth factor, and interleukin-6--promote angiogenesis while one, adiponectin, is inhibitory. Obesity and insulin resistance have both been identified as risk factors for breast cancer and are associated with late-stage disease and poor prognosis. Angiogenesis is essential for breast cancer development and progression, and so it is plausible that obesity-related increases in adipocytokine production and a reduction in adiponectin may adversely affect breast cancer outcome by their angiogenesis-related activities. There is also experimental evidence that some adipocytokines can act directly on breast cancer cells to stimulate their proliferation and invasive capacity. Thus, adipocytokines may provide a biological mechanism by which obesity and insulin resistance are causally associated with breast cancer risk and poor prognosis. Both experimental and clinical studies are needed to develop this concept, and particularly in oestrogen-independent breast cancers where preventive and therapeutic options are limited.
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PMID:Obesity, adipocytokines, and insulin resistance in breast cancer. 1524 84

Hepatocyte growth factor (HGF) is a potent stimulator of angiogenesis and cancer metastasis. Interleukin-6 (IL-6) is a pleiotropic cytokine that can act as an autocrine or paracrine growth factor in various tumor cells. In this study, we investigated the role of serum HGF and IL-6 levels to distinguish primary or metastatic liver tumors from benign liver lesions. Serum HGF and IL-6 levels were measured in 64 cancer patients and 12 healthy controls. Patients were divided into 5 groups: Group-1 (n=24): Breast cancer patients in complete remission without any liver lesion, Group-2 (n=8): Breast cancer patients in complete remission with benign liver lesion, Group-3 (n=10): Breast cancer patients with liver metastasis, Group-4 (n=11): Metastatic breast cancer patients without liver metastasis, Group-5 (n=11): Patients with hepatocellular carcinoma. Group-6 (n=12): Healthy controls. Serum HGF levels were found to be higher in group-5 (606.4+/-255.8 pg/ml) than those in group-1 (*305.6+/-42.3 pg/ml), group-2 (*293.9+/-44.8 pg/ml), group-4 (**358.4+/-81.9 pg/ml) and group-6 (*305.8+/-24.9 pg/ml) (*p<0.001, **p<0.05). Patients in group-3 (448.9+/-157.3 pg/ml) had higher serum HGF levels than those in group-1, group-2 and group-6 (p<0.05). Serum IL-6 levels were found to be higher in group-5 (54.9+/-37.4 pg/ml) than those in group-1 (9.7+/-6.4 pg/ml), group-2 (9.5+/-4.8 pg/ml), group-4 (17.6+/-19.6 pg/ml) and group-6 (12.6+/-5.2 pg/ml, p<0.05). Patients in group-3 (32.5+/-36.9 pg/ml) had higher serum IL-6 levels than those in group-1, 2 and group-6, but these were not statistically significant (p>0.05). This study showed that primer and metastatic liver tumors had higher serum HGF and IL-6 levels than other patients and controls. Measurements of these markers in serum may be used to distinguish patients with primer liver tumors or breast cancer patients with liver metastasis from those with benign liver lesions or non-metastatic patients.
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PMID:Serum hepatocyte growth factor and interleukin-6 levels can distinguish patients with primary or metastatic liver tumors from those with benign liver lesions. 1525 75

Interleukin-6 is a pleiotropic cytokine which plays a crucial role in immune physiology and is tightly controlled by hormonal feedback mechanisms. After menopause or andropause, loss of the normally inhibiting sex steroids (estrogen, testosterone) results in elevated IL6 levels that are further progressively increasing with age. Interestingly, excessive IL6 production promotes tumorigenesis (breast, prostate, lung, colon, ovarian), and accounts for several disease-associated pathologies and phenotypical changes of advanced age, such as osteoporosis, rheumatoid arthritis, multiple myeloma, neurodegenerative diseases and frailty. In this respect, pharmacological modulation of IL6 gene expression levels may have therapeutical benefit in preventing cancer progression, ageing discomforts and restoring immune homeostasis. Although "plant extracts" are used in folk medicine within living memory, it is only since the 20th century that numerous scientific investigations have been performed to discover potential health-protective food compounds or "nutraceuticals" which might prevent cancer and ageing diseases. About 2000 years ago, Hippocrates already highlighted "Let food be your medicine and medicine be your food". Various nutrients in the diet play a crucial role in maintaining an "optimal" immune response, such that deficient or excessive intakes can have negative consequences on the organism's immune status and susceptibility to a variety of pathologies. Over the last few decades, various immune-modulating nutrients have been identified, which interfere with IL6 gene expression. Currently, a broad range of phyto-pharmaceuticals with a claimed hormonal activity, called "phyto-estrogens", is recommended for prevention of various diseases related to a disturbed hormonal balance (i.e. menopausal ailments and/or prostate/breast cancer). In this respect, there is a renewed interest in soy isoflavones (genistein, daidzein, biochanin) as potential superior alternatives to the synthetic selective estrogen receptor modulators (SERMs), which are currently applied in hormone replacement therapy (HRT). As phyto-chemicals integrate hormonal ligand activities and interference with signaling cascades, therapeutic use may not be restricted to hormonal ailments only, but may have applications in cancer chemoprevention and/or NF-kappaB-related inflammatory disorders as well.
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PMID:Soy isoflavone phyto-pharmaceuticals in interleukin-6 affections. Multi-purpose nutraceuticals at the crossroad of hormone replacement, anti-cancer and anti-inflammatory therapy. 1531 15

"Loss of function" alterations in growth inhibitory signal transduction pathways are common in cancer cells. In this study, we show that growth arrest (GA) treatments--serum and growth factor withdrawal and growth inhibitory IL-6 family cytokines (Interleukin-6 and Oncostatin M (OSM))--increase STAT3 phosphorylation (pSTAT3), increase CCAAT enhancer binding protein delta (C/EBPdelta) gene expression and induce GA of primary, finite-lifespan human mammary epithelial cells (HMECs), and immortalized breast cell lines (MCF-10A and MCF-12A). In contrast, serum and growth factor withdrawal from human breast cancer cell lines (MCF-7, SK-BR-3, T-47D, and MDA-MB-231) for up to 48 h induced a relatively modest increase in pSTAT3 levels and C/EBPdelta gene expression and resulted in varying levels of GA. In most breast cancer cell lines, IL-6 family cytokine treatment increased pSTAT3 levels and C/EBPdelta gene expression, however, growth inhibition was cell line dependent. In addition to "loss of function" alterations in growth inhibitory pathways, breast cancer cell lines also exhibit "gain of function" alterations in growth signaling pathways. The Akt growth/ survival pathway is constitutively activated in T-47D and MCF-7 breast cancer cells. The Akt inhibitor LY 294,002 significantly enhanced T-47D growth inhibition by serum and growth factor withdrawal or IL-6 family cytokine treatment. Finally, we show that activation of the pSTAT3/C/EBPdelta growth control pathway is independent of estrogen receptor status. These results demonstrate that "loss of function" alterations in the pSTAT3/C/EBPdelta growth inhibitory signal transduction pathway are relatively common in human breast cancer cell lines. Defective activation of the pSTAT3/ C/EBPdelta growth inhibitory signal transduction pathway, in conjunction with constitutive activation of the Akt growth stimulatory pathway, may play a synergistic role in the etiology or progression of breast cancer.
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PMID:CCAAT/Enhancer binding protein delta (c/EBPdelta) regulation and expression in human mammary epithelial cells: I. "Loss of function" alterations in the c/EBPdelta growth inhibitory pathway in breast cancer cell lines. 1538 79

Breast cancer prognosis differs among racial and ethnic groups. Though the incidence of breast cancer is lower in African-Americans than in Caucasians, mortality is higher. While socioeconomic, psychosocial, and lifestyle issues are undoubtedly important in such disparities, genetic factors that differ among populations and that are involved in the molecular pathways regulating tumor development may also play roles. In this communication, I summarize recent investigations of the gene encoding the pro-inflammatory cytokine interleukin-6 (IL-6), and suggest that this gene is a susceptibility factor that determines racial and/or ethnic differences in breast cancer survival. Published studies of a G/C polymorphism at nucleotide -174 within the promoter region of the IL-6 gene are consistent with this suggestion. This polymorphism alters expression of the cytokine. In addition, allele and genotype frequencies at the -174 site differ dramatically among racial and ethnic groups. Finally, the variant genotypes are associated with alterations in breast cancer survival. In all, these observations argue for additional studies of the IL-6 gene polymorphism as a predisposing genetic factor that contributes to racial and ethnic differences in breast cancer prognosis.
Breast Cancer Res Treat 2004 Dec
PMID:The interleukin-6 gene: a susceptibility factor that may contribute to racial and ethnic disparities in breast cancer mortality. 1560 31

Chemotherapy for breast cancer leads to increased fatigue, poor mood, and reduced quality of life. Few studies have examined possible changes in inflammation during chemotherapy as potential contributors to this phenomenon. This study examined the relationship among circulating levels of soluble intercellular adhesion molecule-1 (sICAM-1), vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) and fatigue, depressed mood, and quality of life before and during anthracycline-based chemotherapy. Twenty-nine women diagnosed with stage I-IIIA breast cancer (mean age 49.5 years, S.D.+/-11) were studied prior to cycle 1 of chemotherapy and 2.5 months later at the start of cycle 4 of chemotherapy. Chemotherapy led to a significant increase in sICAM-1 (P<0.05) and VEGF (P<0.01) levels, as well as increased ratings of fatigue (P<0.01), depressed mood (P<0.03), and poorer quality of life (P<0.01). Multiple regression analyses revealed that elevated VEGF (P<0.01) and sICAM-1 (P<0.02) were related to the increased fatigue and/or poorer quality of life as a result of chemotherapy. Pre-chemotherapy levels of VEGF and pre-chemotherapy ratings of quality of life predicted quality of life in response to chemotherapy (P<0.001). The findings contribute to the literature by showing that both pre-chemotherapy and chemotherapy-induced changes in inflammation are related to changes in fatigue and quality of life in response to chemotherapy.
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PMID:The relationship between fatigue and quality of life and inflammation during anthracycline-based chemotherapy in breast cancer. 1574 Aug 27

About 50% of patients with breast cancer have no involvement of axillary lymph nodes at diagnosis and can be considered cured after primary locoregional treatment. However, about 20-30% will experience distant relapse. The group of patients at risk is not well characterised: recurrence is probably due to the establishment of micrometastases before treatment. Given the early steps of metastasis in which tumour cells interact with endothelial cells of blood vessels, and, given the independent prognostic value in breast cancer of both the quantification of tumour vascularisation and the detection of micrometastases in the bone marrow, the aim of this study was to determine the relationship between vascularisation, measured by Chalkley morphometry, and the bone marrow content of cytokeratin-19 (CK-19) mRNA, quantified by real-time reverse transcriptase polymerase chain reaction, in a series of 68 patients with localised untreated breast cancer. The blood concentration of factors involved in angiogenesis (interleukin-6 and vascular endothelial growth factor) and of factors involved in coagulation (D-dimer, fibrinogen, platelets) was also measured. When bone marrow CK-19 relative gene expression (RGE) was categorised according to the cut-off value of 0.77 (95th centile of control patients), 53% of the patients had an elevated CK-19 RGE. Patients with bone marrow micrometastases, on the basis of an elevated CK-19 RGE, had a mean Chalkley count of 7.5 +/- 1.7 (median 7, standard error [SE] 0.30) compared with a mean Chalkley count of 6.5 +/- 1.7 in other patients (median 6, SE 0.3) (Mann-Whitney U-test; P = 0.04). Multiple regression analysis revealed that Chalkley count, not lymph node status, independently predicted CK-19 RGE status (P = 0.04; odds ratio 1.38; 95% confidence interval 1.009-1.882). Blood parameters reflecting angiogenesis and coagulation were positively correlated with Chalkley count and/or CK-19 RGE. Our data are in support of an association between elevated relative microvessel area of the primary tumour and the presence of bone marrow micrometastases in breast cancer patients with operable disease, and corroborate the paracrine and endocrine role of interleukin-6 and the involvement of coagulation in breast cancer growth and metastasis.
Breast Cancer Res 2005
PMID:Relative microvessel area of the primary tumour, and not lymph node status, predicts the presence of bone marrow micrometastases detected by reverse transcriptase polymerase chain reaction in patients with clinically non-metastatic breast cancer. 1574 2


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