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)

Low expression of the antimetastatic gene nm23 has been associated with shorter overall survival in breast cancer. To better understand the mechanism(s) of action of this protein, we compared the levels of the nm23 protein in 152 breast cancer samples with other factors known to be involved in metastasis or related to prognosis. There was no significant relationship between either of the nm23 isoforms and cathepsin D (Cat-D), urokinase plasminogen activator (uPA), its inhibitor (PAI-1), steroid hormone receptors or ploidy status. A marginal inverse correlation was observed between per cent S-phase and nm23-H1 expression (r = -0.193, P = 0.047) and a positive correlation was observed between uPA receptor (uPAR) and both nm23-H1 (r = 0.263, P = 0.0018) and nm23-H2 (r = 0.230, P = 0.0064). The nm23-H1 gene was transfected into MDA-MB-231 human breast cancer cells and 12 clones were selected, of which two were characterized extensively. We found no significant differences in Cat-D, uPA, PAI-1 or uPAR, as a function of nm23 expression in either the MDA-MB-231 cells or the transfected clones. Compared with the parent cell line, we did observe a dose-dependent decrease in growth factor-stimulated motility and a decrease in metastatic potential in two clones with four- and eightfold elevated nm23-H1 expression, whereas the proliferative activities were similar. We conclude that the decreased metastatic potential might be related to down-regulation of growth factor-stimulated motility.
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PMID:Relationship of nm23 to proteolytic factors, proliferation and motility in breast cancer tissues and cell lines. 974 88

The survival of patients with breast cancer depends on parameters known as prognostic factors. The first generation of prognostic factors are simple, have been validated, and have proved their usefulness. We know the importance of examining axillary lymph nodes. However, because there has been a constant increase in the percentage of patients with no invaded lymph nodes, tumor size has become an important parameter. The 10-year survival rate of patients with tumors less than 1 cm in diameter exceeds 90% suggesting that there might seem to be no need for adjuvant therapy. According to histological grade assessed by the Scarff-Bloom and Richardson method, grade I tumors have a better prognosis than grade II or III tumors. Knowledge of the concentration of estrogen and progesterone receptors in tumors provides not only prognostic information but also indicates whether hormone therapy is justified. All these first generation factors are intimately linked and, taken together, they are the main factors on which the oncologist bases his decision whether or not to prescribe adjuvant therapy. There is still no consensus regarding the assay methods and normal levels of second generation prognostic factors. Amongst these factors, the most promising are those, like S-phase determination by flow cytometry, that evaluate cell proliferation potential and those that investigate tumor invasiveness by assaying urokinase plasminogen activator or its inhibitor.
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PMID:[Prognostic factors and therapeutic strategy of breast cancer]. 978 Dec 9

It is the ability to invade and metastasize that ultimately determines the prognosis in cancer. Comprising one of the key groups of molecules involved in invasion and metastasis are proteases such as urokinase plasminogen activator and cathepsins B, D, and L, as well as various metalloproteases. These proteases catalyze degradation of the interstitial matrix and basement membranes, allowing cancer cells to invade locally and metastasize to distant sites. If proteases are directly and causally involved in cancer spread, they have the potential to be new prognostic markers in cancer. One of the best examples of a correlation between high levels of a protease in a primary tumor and poor prognosis is urokinase plasminogen activation in breast cancer. In this malignancy, the urokinase plasminogen activator is a strong and independent prognostic marker and may be a marker for axillary node-negative disease. The urokinase plasminogen activator may also be a prognostic marker in other cancers such as gastric, colorectal, lung, bladder, cervical, and ovarian cancers. In a number of studies, cathepsin D has been shown to be a prognostic factor in breast cancer. However, results with cathepsin D, especially when immunocytochemistry is used for its detection, are conflicting. Levels of cathepsin B, cathepsin L, and certain metalloproteases may also supply prognostic data in certain cancers, but results with these proteases are still preliminary.
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PMID:Proteases as prognostic markers in cancer. 981 10

Tissue remodeling is a key process involved in normal development, wound healing, bone remodeling, and embryonic implantation, as well as pathological conditions such as tumor invasion and metastasis, and angiogenesis. The degradation of the extracellular matrix that is associated with those processes is mediated by a number of families of extracellular proteinases. These families include the serine proteinases, such as the plasminogen-urokinase plasminogen activator system and leukocyte elastases, the cysteine proteinases, like cathepsin D and L, and the zinc-dependent matrix metalloproteinases (MMPs) [1]. Accumulating evidence has highlighted the central role of MMP-driven extracellular matrix remodeling in mammary gland development and breast cancer.
Breast Cancer Res Treat 1998 Jul
PMID:Roles of the matrix metalloproteinases in mammary gland development and cancer. 982 15

We investigated a potentially central role of protein kinase C (PKC) in controlling multiple pathways in breast cancer cell invasiveness. To do this we evaluated the ability of pharmacologic agents that alter PKC activity to regulate the behavior of the poorly invasive human breast cancer cell line MCF-7. Treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) produced a dramatic induction of the invasiveness of these cells (18-fold), an effect that concurrent treatment with the PKC inhibitor Bryostatin-1 was able to block. To characterize alterations in the cellular properties that might be responsible for these effects we measured the impact of these two agents on a number of processes thought to be important for invasiveness. The motility of the cells was first examined; it was markedly increased by treatment with TPA (20-fold) and again, Bryostatin-1 inhibited this stimulation. We next examined the expression of MMP-1, 3, 9, 10, and 11 (matrix metalloproteinases), all of which have been shown to be PKC responsive in other systems. We found that the expression and secretion of MMP-9 were increased by at least 100-fold, though all of the enzyme secreted was in the latent form. Finally, the expression of both urokinase plasminogen activator (UPA) and its receptor (UPAR) were induced after TPA treatment by 8- and 7-fold, respectively. In conclusion, we have shown that stimulation of PKC activity markedly increases the invasiveness of MCF-7 cells, and that this change in behavior is correlated with a coordinated set of biochemical and cellular changes which are likely to contribute to this process. These data highlight the possible utility of PKC inhibitors such as Bryostatin-1 as anti-invasive and/or antimetastatic agents. Bryostatin-1 is currently in early clinical trials as an anticancer agent.
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PMID:Regulation of motility and protease expression in PKC-mediated induction of MCF-7 breast cancer cell invasiveness. 1004 52

The identification of patients at high risk of relapse is currently one of the most important issues in breast cancer research. However, the selection of high-risk patients continues to be difficult due to the unpredictable course of this disease. Axillary lymph node status is currently recognized as the best clinical discriminant between good and poor prognosis, yet almost 30% of node-negative patients and 65% of node-positive patients will experience a relapse. Additional prognostic markers are therefore urgently needed. Since metastatic disease is the main cause of cancer patient morbidity and mortality, the measurement of molecules functionally involved in the regulation of tumor invasion and metastasis is attractive as a means to predict prognosis. Cancer invasion is a complex process in which degradation of the extracellular matrix plays a crucial role. This degradation is accomplished by the concerted action of several proteolytic enzyme systems, including generation of plasmin by the urokinase pathway of plasminogen activation, matrix metalloproteases, and other extracellular proteases. Increased expression and secretion of urokinase plasminogen activator (uPA) strongly correlates with the malignant phenotype of many types of cells, and the central role of uPA in tumor invasion is now well established. This review will focus on the prognostic impact of components of the urokinase plasminogen activation system in breast cancer with emphasize on methodological issues.
Breast Cancer Res Treat 1998
PMID:The urokinase plasminogen activator system as a target for prognostic studies in breast cancer. 1006 75

Cathepsin B (CB) is a thiol-stimulated protease implicated in cancer invasion and metastasis. Other proteases involved in cancer spread such as urokinase-type plasminogen activator (uPA) and cathepsin D have previously been shown to be prognostic markers in breast cancer. CB was assayed by ELISA in 193 patients with primary breast cancer. CB levels were significantly higher in both primary and metastatic breast tumors than in fibroadenomas (p = 0.0001). In the primary carcinomas, CB levels showed no significant correlation with either nodal status, tumor size or estrogen receptor (ER) status. Patients with primary breast cancers containing high levels of CB had a significantly shorter disease-free interval (p = 0.01, chi-square = 6.61) and overall survival (p = 0.014, chi-square = 6.08) than patients with low levels of the protease. However, in multivariate analysis, using nodal status, tumor size, ER status and urokinase plasminogen activator (uPA), CB was not an independent prognostic marker. In contrast, nodal status, ER status and uPA were prognostic in multivariate analysis. In conclusion, CB, like certain other proteases implicated in cancer metastasis, correlates with poor outcome in patients with breast cancer. These results thus support the evidence from model systems linking CB to cancer spread. Inhibition of CB expression or activity might therefore be exploited for anti-metastatic therapies.
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PMID:High levels of cathepsin B predict poor outcome in patients with breast cancer. 1007 87

We previously showed that thrombospondin 1 (TSP-1) upregulates the plasminogen/plasmin system and promotes breast tumor cell invasion. Preliminary data from our laboratory using neutralizing antibodies suggested that the upregulation in breast tumor cell invasion seen in response to TSP-1 involved the urokinase plasminogen activator receptor (uPAR). To confirm these findings in MDA-MB-231 breast cancer cells, we developed three other strategies to study the role of uPAR in tumor cell adhesion and TSP-1-mediated tumor cell invasion: (a) enzymatic cleavage of uPAR with glycosylphosphatidylinositol-specific phospholipase C; (b) inhibition at the mRNA level with a uPAR antisense construct (cells named LKAS-MDA); (c) inhibition of plasminogen binding with the lysine analogue epsilon-aminocaproic acid. Adhesion to laminin and type I and type IV collagen with and without the addition of epsilon-aminocaproic acid was studied. Tumor cell invasion was studied in a modified Boyden chamber collagen invasion assay. Antisense uPAR inhibition decreased uPAR expression by 48-66% and cell-associated urokinase plasminogen activator (uPA) by 30-68%. Additionally, antisense uPAR inhibition induced a 68-70% reduction in uPA and plasmin activities. Antisense uPAR transfection increased tumor cell adhesion by 46-53%. A similar effect was observed in epsilon-aminocaproic acid-treated MDA-MB-231 cells. TSP-1-mediated tumor cell invasion was almost completely inhibited by either antisense uPAR inhibition or treatment with phospholipase C or epsilon-aminocaproic acid. We conclude that uPAR plays a crucial role in the regulation of tumor cell adhesion and TSP-1-mediated tumor cell invasion.
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PMID:Role of urokinase plasminogen activator receptor in thrombospondin 1-mediated tumor cell invasion. 1009 Aug 48

The transcription factor NF-kappaB regulates the expression of genes involved in cancer cell invasion, metastasis, angiogenesis, and resistance to chemotherapy. In normal cells NF-kappaB is maintained in the cytoplasm by protein-protein interaction with inhibitor IkappaBs. In contrast, in cancer cells a substantial amount of NF-kappaB is in the nucleus and constitutively activates target genes. To understand the mechanisms of constitutive NF-kappaB activation, we have analyzed the function of IkappaBalpha and IkappaBbeta in breast cancer cells. In most cases, constitutive NF-kappaB DNA binding correlated with reduced levels of either IkappaBalpha or IkappaBbeta isoforms. Overexpression of IkappaBalpha but not IkappaBbeta1 resulted in reduced constitutive DNA binding of NF-kappaB in MDA-MB-231 cells. Unexpectedly, IkappaBbeta1 overexpression moderately increased 12-O-tetradecanoylphorbol-13-acetate- and interleukin-1-inducible NF-kappaB DNA binding. 12-O-Tetradecanoylphorbol-13-acetate- and interleukin-1-induced transactivation by NF-kappaB, however, was lower in IkappaBbeta1-overexpressing cells. Mutants of IkappaBbeta1 lacking the C-terminal casein kinase II phosphorylation sites, which form a stable complex with DNA bound NF-kappaB without inhibiting its transactivation in other cell types, repressed the transactivation by NF-kappaB in MDA-MB-231 cells. Consistent with the results of transient transfections, the expression of urokinase plasminogen activator, an NF-kappaB target gene, was reduced in IkappaBbeta1-overexpressing cells. These results suggest that depending on the cell type, IkappaBbeta1 represses the expression of NF-kappaB-regulated genes by inhibiting either DNA binding or transactivation function of NF-kappaB.
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PMID:Negative regulation of transactivation function but not DNA binding of NF-kappaB and AP-1 by IkappaBbeta1 in breast cancer cells. 1037 1

Cytosolic determinations of cathepsin-D (cath-D), urokinase plasminogen activator (uPA) and its specific inhibitor PAI-1 have shown an association with adverse prognosis in breast cancer. Our aim was to study the distribution of these markers in small axillary node-negative breast carcinomas using immunohistochemistry and relate the semiquantitative results to known prognostic factors, the expression of tenascin-C (Tn-C) in invasion border of the tumour and prognosis. All the 158 women (159 tumours) were treated with breast conserving surgery and postoperative radiotherapy. Cytoplasmic immunoreactivity for cath-D was seen in carcinoma cells in 47% and in stromal cells in 44%. Nearly all tumours expressed uPA and PAI-1, which were categorized to cytoplasmic expression in carcinoma cells and diffuse stromal expression and quantified -/+/++/ and further dichotomized for purposes of analysis. Expression of uPA and PAI-1 in stromal fibroblasts was recorded as -/+. Cytoplasmic and stromal cell cath-D contents were associated with grade, proliferation, Tn-C expression in the tumour invasion border and the development of distant metastasis. In multivariate analysis stromal cath-D proved to be an independent prognostic factor for metastasis. Stromal expression of uPA was associated with an increased risk of local recurrence; otherwise high levels of uPA did not associate with other prognostic factors nor with prognosis. Fibroblastic expression of PAI-1 showed an association with both local and distant disease recurrence. However, no consistent association between the immunohistochemically quantified uPA and PAI-1 and prognosis was found. In conclusion, immunohistochemical determination of cath-D seems to be a viable method to predict a higher risk of metastasis but not local recurrence in small axillary node-negative breast carcinomas.
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PMID:Cathepsin-D, urokinase plasminogen activator and type-1 plasminogen activator inhibitor in early breast cancer: an immunohistochemical study of prognostic value and relations to tenascin-C and other factors. 1038 93


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