Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Use of non-steroid anti-inflammatory drugs (NSAIDs) has been associated with decreased risk of breast cancer in epidemiological studies. Thus, a high-inflammatory response may be associated with increased breast cancer risk. It is thus possible that genetic variations leading to a modified inflammatory response will influence breast cancer risk. The purpose of this study was to determine if polymorphisms associated with an altered inflammatory response are associated with breast cancer risk, and to investigate the possible interaction with lifestyle factors such as alcohol use, smoking and NSAID use. We matched 361 female breast cancer cases with 361 controls, nested within the prospective 'Diet, Cancer and Health' study. Carriers of the variant Ala-allele of PPARgamma2 Pro12Ala were at lower risk of breast cancer (IRR=0.67, 95% CI=0.46-0.97). This was primarily due to an interaction with alcohol consumption. Alcohol consumption was associated with a 1.21-fold increased risk of breast cancer per 10 g alcohol/day (95% CI=1.06-1.35) among homozygous wild-type carriers, whereas alcohol was not associated with breast cancer risk among variant allele carriers (P for interaction=0.005). Non-users of NSAID, who were carriers of the variant allele of PPARgamma2 Pro12Ala, were at lower risk of breast cancer (IRR=0.44; 95% CI=0.26-0.73) compared with non-users carrying wild-type alleles (P for interaction=0.03). No effects were found for IL6 G-174C, IL8 T-251A and COX2 T8473C. Our results suggest that PPARgamma2 Pro12Ala is an important determinant in alcohol mediated breast carcinogenesis. We also observe interaction between NSAID, alcohol consumption and PPARgamma2 Pro12Ala genotype in relation to breast cancer risk.
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PMID:Peroxisome proliferator-activated [corrected] receptor-gamma2 [corrected] Pro12Ala, interaction with alcohol intake and NSAID use, in relation to risk of breast cancer in a prospective study of Danes. 1695 87

Human mammary epithelial cells (HMECs) exhibit an increase in phosphocholine (PC) and total choline-containing compounds, as well as a switch from high glycerophosphocholine (GPC)/low PC to low GPC/high PC, with progression to malignant phenotype. The treatment of human breast cancer cells with a nonsteroidal anti-inflammatory agent, indomethacin, reverted the high PC/low GPC pattern to a low PC/high GPC pattern indicative of a less malignant phenotype, supported by decreased invasion. Here, we have characterized mechanisms underlying indomethacin-induced alterations in choline membrane metabolism in malignant breast cancer cells and nonmalignant HMECs labeled with [1,2-13C]choline using 1H and 13C magnetic resonance spectroscopy. Microarray gene expression analysis was performed to understand the molecular mechanisms underlying these changes. In breast cancer cells, indomethacin treatment activated phospholipases that, combined with an increased choline phospholipid biosynthesis, led to increased GPC and decreased PC levels. However, in nonmalignant HMECs, activation of the anabolic pathway alone was detected following indomethacin treatment. Following indomethacin treatment in breast cancer cells, several candidate genes, such as interleukin 8, NGFB, CSF2, RHOB, EDN1, and JUNB, were differentially expressed, which may have contributed to changes in choline metabolism through secondary effects or signaling cascades leading to changes in enzyme activity.
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PMID:Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. 1698 33

Procathepsin D (pCD) is a major secreted protein in estrogen receptor-positive (ER+) breast cancer cell lines. Several independent studies have documented pronounced mitogenic effect of secreted pCD on cancer tissue-derived cell lines, including those from breast, lung, and prostate cancer. It has also been shown that the proliferative effect of pCD involves both autocrine and paracrine modes of action. Recent studies have suggested that pCD could act as a key paracrine communicator between cancer and stromal cells. We have shown earlier that the proliferative activity of pCD depends on the activation peptide sequence of pCD. The present study casts light on the mechanism by which pCD influences the proliferation of cancer cells expressing the ER. Results described in the current paper clearly show that pCD initiates secretion of cytokines interleukin-4 (IL-4), IL-8, IL-10, IL-13, macrophage inflammatory protein-1beta and (MIP-1beta) from such tumor cells. Secreted cytokines take part in the proliferation of the cancer cells, as proven by selective inhibition using antibodies. In addition, expression of cytokine receptors on tested cell lines corresponded to the effects of individual cytokines. An analogous pattern was also observed for fibroblasts, which, under physiologic conditions, are the cells in closest contact with the tumor tissue and play a role in tumor growth and invasion. Our observations were further supported by coculture experiments that are in agreement. Although very similar in response to addition of pCD, the invasive ER- cells do not secrete cytokines. Together with previous in vivo results, these data point to pCD as one of key molecules for therapeutic attack in breast cancer.
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PMID:Secretion of cytokines in breast cancer cells: the molecular mechanism of procathepsin D proliferative effects. 1734 17

Identification of genes/proteins that are differentially expressed in HER2 (erbB-2) oncogene-dependent breast carcinomas is essential in elucidating the mechanistic basis of their increased metastastic potential and resistance to several anti-cancer therapies. We here applied human cytokine antibody arrays with the goal of identifying a unique HER2-induced 'cytokine signature' in breast cancer. Human Cytokine Array III (RayBiotech, Inc.), which simultaneously detects 42 cytokines and growth factors on one membrane, was used to determine the profile of cytokines in conditioned media obtained from MCF-7/Her2-18 cells, a MCF-7-derived clone engineered to stably express the full-length human HER2 cDNA controlled by a SV40 viral promoter, and from the MCF-7/neo control sub-line. We identified two inflammatory and pro-angiogenic CXC chemokines with at least a 10-fold increased expression in HER2-overexpressing MCF-7/Her2-18 transfectants when compared to matched control MCF-7/neo cells: CXCL8 (IL-8; Interleukin-8) and CXCL1 and (GRO; Growth-related oncogene). HER2-induced differential overexpression of IL-8 and GRO was validated by ELISA and further confirmed by switching off the HER2 signalling. Treatment with the tyrosine kinase inhibitor gefitinib (Iressa) returned the expression levels of IL-8 and GRO back to the baseline observed in MCF-7 breast cancer cells, which express physiological levels of HER2. To evaluate the diagnostic utility of these findings, cytokine-specific antibody arrays were incubated with sera retrospectively collected from metastatic breast cancer patients. This approach revealed a high similarity between the 'cytokine signature' observed in serum samples and that obtained in media conditioned by breast cancer-derived cell lines. Thus, IL-8 and GRO circulating levels were significantly higher in HER2-positive breast cancer patients compared with HER2-negative patients. These findings reveal for the first time that: a) Enhanced synthesis and secretion of members of the IL-8/GRO chemokine family, which have recently been linked to oestrogen receptor (ER) inaction, increased cell invasion and angiogenesis, may represent a new pathway involved in the metastatic progression and endocrine resistance of HER2-overexpressing breast carcinomas, and b) Circulating levels of IL-8 and GRO cytokines may represent novel biomarkers monitoring breast cancer responses to endocrine treatments and/or HER2-targeted therapies.
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PMID:Protein array technology to detect HER2 (erbB-2)-induced 'cytokine signature' in breast cancer. 1737 3

Ecto-5'-nucleotidase (CD73) was overexpressed in malignancies of epithelial origin and was involved in a variety of cellular processes such as cytoprotection and anti-inflammation. In the present study, human mammary T-47D cells were transfected with pcDNA-NT5E to establish a CD73 overexpressed cell model. Short small interfering RNA (siRNA) was used to silence the epidermal growth factor receptor (EGFR) gene. Real-time PCR, RT-PCR and western-blot were used to study CD73 and EGFR expression. Surface CD73 activity was assessed by quantifying the conversion of etheno-AMP to ethenoadenosine via HPLC. Interleukin (IL)-8 mRNA and protein expression were analyzed by RT-PCR and ELISA. Cell motility, invasiveness and adhesion to extracellular matrix (ECM) were measured by in vitro invasion and adhesion assay before and after transfection. We demonstrated that abilities of migration, invasions and adhesion to ECM in pcDNA-NT5E transfected T-47D cells increased significantly, which can be blocked by CD73 inhibitor alpha, beta-methylene ADP(APCP). Addition of adenosine reversed the effects of APCP. The mRNA and protein expression of EGFR and IL-8 increased in pcDNA-NT5E transfected T-47D cells. EGFR siRNA down-regulated EGFR expression dramatically, leading to migration and invasion activities inhibition in pcDNA-NT5E transfected T-47D cells. Our results suggest that up-regulated adenosine production, EGFR and IL-8 expression due to overexpressed CD73 may involved in CD73-promoted breast cancer metastasis.
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PMID:Overexpression of Ecto-5'-nucleotidase (CD73) promotes T-47D human breast cancer cells invasion and adhesion to extracellular matrix. 1747 Oct 30

The prognostic significance of supplementing co-enzyme Q(10) (CoQ(10)), riboflavin and niacin (CoRN) along with tamoxifen to breast cancer patients was evaluated by measuring the serum cytokine levels of interleukin (IL)-1beta, IL-6, IL-8, tumour necrosis factor alpha (TNF-alpha) and vascular endothelial growth factor. In the present study, 84 breast cancer patients were randomized to receive a daily supplement of CoQ(10) 100 mg, riboflavin 10 mg and niacin 50 mg, one dosage per day along with tamoxifen 10 mg twice a day. Serum cytokine levels were elevated in untreated breast cancer patients (Group II) and significantly reduced after tamoxifen therapy for more than 1 year (Group III). When group III breast cancer patients were supplemented with CoRN for 45 days (Group IV) and 90 days (Group V) along with tamoxifen, a significant reduction in cytokine levels were observed (P < 0.05). Such a decrease in serum cytokine levels after CoRN supplementation in breast cancer patients may suggest good prognosis and efficacy of the treatment, and might even offer protection from metastases and recurrence of cancer.
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PMID:Serum cytokine levels of interleukin-1beta, -6, -8, tumour necrosis factor-alpha and vascular endothelial growth factor in breast cancer patients treated with tamoxifen and supplemented with co-enzyme Q(10), riboflavin and niacin. 1751 92

Macrophage polarization contributes to a number of human pathologies. This is exemplified for tumor-associated macrophages (TAMs), which display a polarized M2 phenotype, closely associated with promotion of angiogenesis and suppression of innate immune responses. We present evidence that induction of apoptosis in tumor cells and subsequent recognition of apoptotic debris by macrophages participates in the macrophage phenotype shift. During coculture of human primary macrophages with human breast cancer carcinoma cells (MCF-7) the latter ones were killed, while macrophages acquired an alternatively activated phenotype. This was characterized by decreased tumor necrosis factor (TNF)-alpha and interleukin (IL) 12-p70 production, but increased formation of IL-8 and -10. Alternative macrophage activation required tumor cell death because a coculture with apoptosis-resistant colon carcinoma cells (RKO) or Bcl-2-overexpressing MCF-7 cells failed to induce phenotype alterations. Interestingly, phenotype alterations were achieved with conditioned media from apoptotic tumor cells, arguing for a soluble factor. Knockdown of sphingosine kinase (Sphk) 2, but not Sphk1, to attenuate S1P formation in MCF-7 cells, restored classical macrophage responses during coculture. Furthermore, macrophage polarization achieved by tumor cell apoptosis or substitution of authentic S1P suppressed nuclear factor (NF)-kappaB signaling. These findings suggest that tumor cell apoptosis-derived S1P contributes to macrophage polarization.
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PMID:Tumor cell apoptosis polarizes macrophages role of sphingosine-1-phosphate. 1765 60

Interleukins (ILs) are known to play a fundamental role in cancer. We investigated the serum levels of IL-8 and IL-12, in breast cancer patients, and their relationship with the prognostic parameters and therapy. Forty eight patients with pathologically verified breast carcinoma and 21 healthy controls were enrolled into the study. Serum samples were obtained at baseline and after two cycles of chemotherapy. Serum IL-8 and IL-12 levels were determined using enzyme-linked immunosorbent assay (ELISA). There was no significant difference in the baseline serum IL-8 and IL-12 levels between breast cancer patients and healthy controls (p = 0.365 and p = 0.871, respectively), no significant correlation between the prognostic parameters and the serum IL-8, IL-12 levels. However, in the subgroup consisting of metastatic breast cancer patients, baseline serum IL-8 levels were significantly higher compared with non-metastatic disease (p = 0.047). Anthracycline-based chemotherapy and the addition of taxane did not change the levels of both serum IL-8 and IL-12. Serum IL-8 level may be useful in determining metastatic breast cancer. Larger studies are needed to confirm this finding.
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PMID:Serum IL-8 and IL-12 levels in breast cancer. 1784 39

The estrogen receptor (ER) protects against debilitating effects of the inflammatory response by inhibiting the proinflammatory transcription factor nuclear factor-kappaB (NFkappaB). Heretofore cAMP response element-binding protein (CREB)-binding protein (CBP) has been suggested to mediate inhibitory cross talk by functioning either as a scaffold that links ER and NFkappaB or as a required cofactor that competitively binds to one or the other transcriptional factor. However, here we demonstrate that ER is recruited to the NFkappaB response element of the MCP-1 (monocyte chemoattractant protein-1) and IL-8 promoters and displaces CBP, but not p65, in the MCF-7 breast cancer cell line. In contrast, ER displaced p65 and associated coregulators from the IL-6 promoter, demonstrating a gene-specific role for CBP in integrating inflammatory and steroid signaling. Further, RNA interference and overexpression studies demonstrated that CBP dosage regulates estrogen-mediated suppression of MCP-1 and IL-8, but not IL-6, gene expression. This work further demonstrates that CBP dosage is a critical regulator of gene-specific signal integration between the ER- and NFkappaB-signaling pathways.
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PMID:CBP Is a dosage-dependent regulator of nuclear factor-kappaB suppression by the estrogen receptor. 1793 6

A case-control study involving 257 breast cancer patients with invasive ductal carcinoma and 233 healthy women was carried out to explore if the IL-8 -251T/A polymorphism and the CXCR2 +1208 C/T polymorphism have a role in breast cancer susceptibility. Genotypic analysis showed an increased frequency of high producer IL-8 -251AA genotype (p=0.016) in the patient group as compared to controls while CXCR2 +1208 C/T polymorphism did not show any differences between studied groups. However, in contrast to IL-8 -251 polymorphism, the percentage of CXCR2 +1208 TT genotype was significantly lower in patients with NPI<or=3.4 compared to NPI>3.4 (2% and 12%, respectively; p=0.03). Also, ER- tumors showed an approximately significant higher CXCR2 +1208 TT genotype compared to ER+ tumors (18.6% and 7.1%, respectively; p=0.07). In conclusion, IL-8 -251T/A polymorphism is associated with development of invasive ductal carcinoma type of breast cancer while CXCR2 +1208C/T polymorphism may affect the disease progression.
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PMID:Association of interleukin-8 (IL-8 or CXCL8) -251T/A and CXCR2 +1208C/T gene polymorphisms with breast cancer. 1794 31


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