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)

Parathyroid hormone-related protein (PTHrP) is expressed in the mammary gland and appears to be critical to the morphogenesis of this structure. PTHrP production in the breast is generally attributed to epithelial cells. Because the stromal component of the breast produces factors implicated in proliferation and differentiation of mammary epithelial tissue and tumors, the aim of this study was to investigate the PTHrP expression by mammary fibroblasts from breast cancer tumors and normal breast. PTHrP antibodies labeled intralobular fibroblasts in normal breast and stromal fibroblasts that surround tumor cells. PTHrP was constitutively produced by the cultured mammary fibroblasts, independent of serum stimulation. Normal (15.83 +/- 1.72 fmol/10(6) cells) and pathological breast fibroblasts (19.87 +/- 5.76) secreted similar amounts of PTHrP. PTH/PTHrP receptor mRNA was detected by RT-PCR in all the samples tested. Fibroblasts from normal breast were both PTH and PTHrP-cAMP responsive (453 +/- 133% and 513 +/- 133%, respectively, from basal stimulation), whereas pathological breast fibroblasts were minimally PTHrP-cAMP responsive (183 +/- 36%). The production of other fibroblastic factors implicated in tumor growth and invasiveness was also examined. Interleukin-6 (IL-6), tumor necrosis factor-alpha (INF-alpha), and pro-matrix metalloproteinase (MMP)-1 were not affected by the status of the tissue. In contrast, increased levels of pro-MMP-2 were produced in fibroblasts that originated from pathological (290 +/- 62 ng/10(6) cells) samples compared with those from normal donors (125 +/- 41 ng/10(6) cells). PTHrP production was correlated with TNF-alpha and pro-MMP-2 production. However, inhibition with specific neutralizing antibodies against TNF-alpha or PTHrP, or with a PTHrP antagonist, showed that these factors did not regulate each other. In conclusion, breast fibroblasts are constitutive PTHrP-producing cells with the potential for autocrine signaling through the PTH/PTHrP receptor.
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PMID:Constitutive production of parathyroid hormone-related protein (PTHrP) by fibroblasts derived from normal and pathological human breast tissue. 1254 23

Mastalgia is a common condition that is thought to be hormonally related, but the mechanisms of pain causation are unknown. Inflammatory cytokines are implicated in pain modulation, but have not been studied with regard to mastalgia. We compared the relationship of mastalgia to the expression of the cytokines interleukin (IL)-6, IL-1beta, and tumor necrosis factor (TNF)-alpha and the degree of tissue infiltration with inflammatory cells in breast tissue from 29 premenopausal women with breast pain and 29 age-matched pain-free controls. Paraffin sections from breast biopsy samples were scored for the presence of inflammatory infiltrate and were evaluated for the expression of IL-6, IL-1beta, and TNF-alpha using standard immunohistochemical procedures. TNF-alpha and IL-6 expression displayed a trend toward slightly lower values in patients with pain (median TNF-alpha score, 3 versus 5; median IL-6 score, 3 versus 4). In the luteal phase, patients with mastalgia showed a trend toward lower expression of IL-6 (p = 0.4) in comparison to those without pain. A similar trend was also seen with TNF-alpha expression (p = 0.4). IL-1beta expression was extremely scant in the first 30 samples and was not investigated further. The degree of inflammatory infiltrate in the tissue was unrelated to the presence of breast pain. These data suggest that the three cytokines tested in this study do not play a significant role in the causation of mastalgia and lend weight to the previous finding that there are no identifiable histologic correlates of this troubling condition. Further investigation of the role of cytokines in breast pain is warranted, especially in view of the possible association between mastalgia and breast cancer risk.
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PMID:Expression of interleukin-6 and tumor necrosis factor alpha and histopathologic findings in painful and nonpainful breast tissue. 1260 81

Onset of the mitochondrial permeability transition (MPT) causes both necrotic and apoptotic cell death in cultured hepatocytes. Salicylate lowers the threshold for onset of the MPT. In this study, our aim was to determine whether nontoxic concentrations of salicylate potentiate MPT-mediated cell killing. In necrotic killing models to rat hepatocytes, salicylate (1 mM) enhanced calcium ionophore (Br-A23187)- and tert-butylhydroperoxide (t-BuOOH)-induced cell death, which was blocked or delayed by cyclosporin A (CsA, 2 microM), a specific inhibitor of the MPT. In hepatocyte apoptosis induced by tumor necrosis factor-alpha (TNF-alpha), salicylate accelerated cell killing after low-dose TNF-alpha (1 ng/ml), which by itself induced little apoptosis. Salicylate enhancement of apoptosis was associated with onset of the MPT and accelerated caspase 3 activation. Salicylate also augmented killing of MCF-7 human breast tumor cells by etoposide and PLC/PRF/5 human hepatoma cells by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In conclusion, salicylate potentiates both necrotic and apoptotic cell killing by promoting onset of the MPT. Enhancement by salicylate of MPT-dependent apoptosis may play a role in protection by aspirin and other nonsteroidal anti-inflammatory drugs against colon, lung, and breast cancer.
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PMID:Salicylate enhances necrosis and apoptosis mediated by the mitochondrial permeability transition. 1270 Apr 12

Interleukin-6 (IL-6) and interleukin-11 (IL-11) are frequently produced by breast cancer cells. These interleukins promote osteoclast formation and may mediate osteolysis at the site of breast cancer bone metastases. Transforming growth factor-beta (TGF-beta), tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) up-regulate IL-6 and IL-11 production in a cytokine-dependent fashion in breast cancer cells, but very little is known about their intracellular signaling pathways in breast cancer cells. To study TGF-beta, TNF-alpha and IL-1beta regulation of IL-6 and IL-11 production in human MDA-MB-231 breast cancer cells, we established single cell clones stably expressing dominant negative (DN) forms of the mitogen-activated protein kinases p38 (p38/AF) or ERK1 (ERK1K71R). We show here, that while basal, TGF-beta and IL-1beta induced IL-6 production was similar in parental cells and in pcDNA3 control, ERK1K71R and p38/AF clones, TNF-alpha induced IL-6 production was blunted in the ERK1K71R clones. TGF-beta and IL-1beta, but not TNF-alpha, induced IL-11 production in parental MDA-MB-231 cells. Similar findings were detected in clones stably expressing p38/AF and ERK1K71R, which did not change basal IL-11 production either. In conclusion, TNF-alpha induced IL-6 production is mediated via ERK1 activation in MDA-MB-231 cells. These observations may be helpful in designing new anti-osteolytic therapies.
Breast Cancer Res Treat 2003 Jul
PMID:Tumor necrosis factor-alpha induces interleukin-6 production via extracellular-regulated kinase 1 activation in breast cancer cells. 1288

The MCF-7 cell line was derived from a patient with metastatic breast cancer in 1970. Since then it has become a prominent model system for the study of estrogen receptor-positive breast cancer. With this model as a focus, this review summarizes important studies addressing tumor necrosis factor-alpha as a prototypical apoptosis-inducing cytokine in MCF-7 cells. Both survival and death receptor signaling pathways are discussed in terms of their role in chemotherapy-induced apoptosis as well as in chemoresistance. Novel therapeutic approaches to the treatment of breast cancer are proposed utilizing knowledge of these signaling pathways as targets. Specifically, ceramide metabolism is proposed as a novel target for chemosensitivity, perhaps combined with selective inhibitors of Bcl-2 or PI3K/Akt/nuclear factor-kappaB. Suggested areas of future research include translational studies manipulating candidate survival and death signaling pathways.
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PMID:Apoptosis, chemoresistance, and breast cancer: insights from the MCF-7 cell model system. 1453 May 7

Phosphatidylinositol (PI) 3-kinase/Akt signaling activates NF-kappa B through pleiotropic, cell type-specific mechanisms. This study investigated the significance of PI 3-kinase/Akt signaling to tumor necrosis factor (TNF)-induced NF-kappa B activation in transformed, immortalized, and primary cells. Pharmacological inhibition of PI 3-kinase blocked TNF-induced NF-kappa B DNA binding in the 293 line of embryonic kidney cells, partially affected binding in MCF-7 breast cancer cells, HeLa and ME-180 cervical carcinoma cells, and NIH 3T3 cells but was without significant effect in H1299 and human umbilical vein endothelial cells, cell types in which TNF activated Akt. NF-kappa B is retained in the cytoplasm by inhibitory proteins, I kappa Bs, which are phosphorylated and targeted for degradation by I kappa B kinases (IKK alpha and IKK beta). Expression and the ratios of IKK alpha and IKK beta, which homo- and heterodimerize, varied among cell types. Cells with a high proportion of IKK alpha (the IKK kinase activated by Akt) to IKK beta were most sensitive to PI 3-kinase inhibitors. Consequently, transient expression of IKK beta diminished the capacity of the inhibitors to block NF-kappa B DNA binding in 293 cells. Also, inhibitors of PI 3-kinase blocked NF-kappa B DNA binding in Ikk beta-/- but not Ikk alpha-/- or wild-type cells in which the ratio of IKK alpha to IKK beta is low. Thus, noncoordinate expression of I kappa B kinases plays a role in determining the cell type-specific role of Akt in NF-kappa B activation.
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PMID:Cell type-specific expression of the IkappaB kinases determines the significance of phosphatidylinositol 3-kinase/Akt signaling to NF-kappa B activation. 1458 46

Progression of breast cancer involves cross-talk between epithelial and stromal cells. This cross-talk is mediated by growth factors and cytokines secreted by both cancer and stromal cells. We previously reported expression of interleukin (IL)-1 alpha in a subset of breast cancers and demonstrated that IL-1 alpha is an autocrine and paracrine inducer of prometastatic genes in in vitro systems. To understand the role of IL-1 alpha in breast cancer progression in vivo, we studied the growth of MCF-7 breast cancer cells overexpressing a secreted form of IL-1 alpha (MCF-7IL-1 alpha) in nude mice. MCF-7IL-1 alpha cells formed rapidly growing estrogen-dependent tumors compared to parental cells. Interestingly, IL-1 alpha expression alone was not sufficient for metastasis in vivo although in vitro studies showed induction of several prometastatic genes and matrix metalloproteinase activity in response to cross-talk between IL-1 alpha-expressing cancer cells and fibroblasts. Animals implanted with MCF-7IL-1 alpha cells were cachetic, which correlated with increased leptin serum levels but not other known cachexia-inducing cytokines such as IL-6, tumor necrosis factor, or interferon gamma. Serum triglycerides, but not blood glucose were lower in animals with MCF-7IL-1 alpha cell-derived tumors compared to animals with control cell-derived tumors. Cachexia was associated with atrophy of epidermal and adnexal structures of skin; a similar phenotype is reported in triglyceride-deficient mice and in ob/ob mice injected with leptin. Mouse leptin-specific transcripts could be detected only in MCF-7IL-1 alpha cell-derived tumors, which suggests that IL-1 alpha increases leptin expression in stromal cells recruited into the tumor microenvironment. Despite increased serum leptin levels, animals with MCF-7IL-1 alpha cell-derived tumors were not anorexic suggesting only peripheral action of tumor-derived leptin, which principally targets lipid metabolism. Taken together, these results suggest that cancer cell-derived cytokines, such as IL-1 alpha, induce cachexia by affecting leptin-dependent metabolic pathways.
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PMID:Interleukin-1 alpha promotes tumor growth and cachexia in MCF-7 xenograft model of breast cancer. 1463 25

Recent evidence suggests a role for aberrant ceramide levels in the pathogenesis of cancer and chemoresistance and indicates that manipulation of tumor ceramide levels may be a useful strategy in the fight against breast cancer. This study demonstrates that alterations in the degree and position of unsaturation of bonds in the sphingoid backbone of d-erythro-N-octanoyl-sphingosine (Cer) affect the antiproliferative ability of ceramide analogs in breast cancer cells. The most potent analog of Cer we tested is (2S,3R)-(4E,6E)-2-octanoylamidooctadecadiene-1,3-diol (4,6-diene-Cer), which contains an additional trans double bond at C(6)-C(7) of the sphingoid backbone. 4,6-Diene-Cer exhibited higher potency than Cer in tumor necrosis factor (TNF)-alpha-resistant (IC(50) of 11.3 versus 32.9 microM) and TNF-alpha-sensitive (IC(50) of 13.7 versus 37.7 microM) MCF-7 cells. 4,6-Diene-Cer was also more potent than Cer in inducing cell death in MDA-MB-231 and NCI/ADR-RES breast cancer cell lines (IC(50) of 3.7 versus 11.3 microM, and 24.1 versus 86.9 microM, respectively). 4,6-Diene-Cer caused a prolonged elevation of intracellular ceramide levels in MCF-7 cells, which may contribute to its enhanced cytotoxicity. Furthermore, treatment of MCF-7 cells with Cer or 4,6-diene-Cer resulted in induction of apoptosis by 8 h via the mitochondrial pathway, as demonstrated by release of cytochrome c, loss of membrane asymmetry (measured by Annexin V staining), and a decrease in the mitochondrial membrane potential. Importantly, both Cer and 4,6-diene-Cer displayed selectivity toward transformed breast cells over nontransformed breast epithelial cells. These data suggest that these and other novel ceramide analogs represent potential therapeutic agents in breast cancer treatment.
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PMID:Novel ceramide analogs as potential chemotherapeutic agents in breast cancer. 1474 41

The fusion of a murine B cell and a myeloma cell generates a hybridoma that produces monoclonal antibody (mAb). These murine mAb induce the HAMA (human anti-mouse antibodies) response. Murine mAb have been modified by genetic engineering, producing molecules with a higher proportion of human protein. At present, chimeric, humanized and fully human mAb are available. mAb block interactions between target molecules and their ligands or trigger the lyses of mAb-coated tumor cells. Numerous mAb have been developed using the recombinant DNA technology and several are available in the market. Trastuzumab, against HER2/neu, is useful in breast cancer; rituximab, against CD20 in B lymphocytes is useful in lymphoma; alemtuzumah, against CD52 is used in lymphoma and leukemia; daclizumab and basiliximab block the IL-2 receptor interaction and reduce acute rejection in kidney transplantation; abciximab, an antagonist of GPIIb/IIIa platelet receptor, is used in patients undergoing acute coronary syndromes. In autoimmunity diseases, blocking tumor necrosis factor by infliximab and adalimumab has demonstrated excellent results. Thus, infliximab is useful in the treatment of rheumatoid arthritis (RA), Crohn's disease and ulcerative colitis while adalimumab is the first fully human mAb available for RA. Infliximab and adalimumab reduce signs and symptoms in RA and they also interfere with progression of joint damage. Finally, the direct benefits of antagonist treatment can occur at the expense of a major adverse effect in some other biological function.
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PMID:[New immunological weapons for medicine in the 21st Century: biological therapy based on the use of the latest generation monoclonal antibodies]. 1502 9

The epidemiological data suggest that breast cancer risk decreases in women who complete full-term pregnancy at a young age. Studies on a rat breast cancer model indicate that human chorionic gonadotropin (hCG), a hormone that is present in very high levels during pregnancy, could be responsible for this decrease. These findings, as well as those demonstrating the presence of functional luteinizing hormone (LH)/hCG receptors in human breast cells, prompted us to investigate the anti-proliferative and anti-invasive effects of hCG in human breast cancer MCF-7 cells by down-regulating NF-kappaB and AP-1 transcription factors. Treatment of MCF-7 cells with highly purified hCG resulted in a modest dose-dependent and hormone-specific decrease in cell proliferation. hCG treatment also decreased cell invasion, which was more dramatic than the decrease in cell proliferation. These hCG actions were abrogated when receptor synthesis was inhibited by treatment with antisense hCG/LH receptor phosphorothioate oligodeoxynucleotide. hCG treatment prevented the tumor necrosis factor-dependent NF-kappaB and AP-1 activation, which paralleled a decrease in the phosphorylation and degradation of IkappaBalpha. The findings that hCG treatment increased cAMP synthesis and activated cAMP-dependent protein kinase, dibutyryl cAMP mimicked hCG in preventing NF-kappaB activation, and dideoxyadenosine, an adenylate cyclase inhibitor, prevented the hCG effect on NF-kappaB suggested that the hCG actions are mediated via the cAMP-dependent protein kinase A signaling pathway. In summary, our results demonstrate that hCG has anti-proliferative and anti-invasive effects in MCF-7 cells by down-regulating NF-kappaB and AP-1. These findings support the premise that hCG could be responsible for the pregnancy-induced protection against breast cancer in women.
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PMID:Human chorionic gonadotropin decreases proliferation and invasion of breast cancer MCF-7 cells by inhibiting NF-kappaB and AP-1 activation. 1504 47


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