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)

There remains a number of unmet clinical needs in patients with breast cancer that research and development aims to address. More sensitive and specific indicators of prognosis are required to identify those patients at greatest risk for disease progression. A number of biological markers including the cyclins, circulating epithelial cells, and components of the urokinase plasminogen system have been shown to correlate with patient outcome. Genomic analysis also has the potential to predict patient response to specific agents, thus ensuring patients derive the maximum benefit from the treatment they receive. Patients who require treatment are often exposed to the undesirable toxic effects that are associated with some treatments. Liposomal and nanoparticle formulations of currently available agents have been shown to be at least as effective as their parent compounds but with improved safety and tolerability profiles. Studies into patient quality of life during therapy have highlighted the importance of early administration of an erythropoietic agent to treat chemotherapy-induced anemia. Further research in breast cancer should further optimize the treatment patients receive ensuring that patients not only live longer but also have quality survival.
Breast Cancer Res Treat 2005
PMID:The future of breast cancer: the role of prognostic factors. 1577 May 35

The serine protease uPA (urokinase-type plasminogen activator) and its receptor uPAR (CD87) are often elevated in malignant tumours, hence, inhibition of this tumour-associated plasminogen activation system provides an attractive target for therapeutic strategies. WX-UK1, a derivative of 3-aminophenylalanine in the L-conformation with inhibitory antiproteolytic properties, was tested for its specificity spectrum using specific chromogenic paranitroanilide peptide substrates. The corresponding D-enantiomer of WX-UK1 was used as a control. The anti-tumour and anti-metastatic (number of lung foci and weight of the axillary lymph nodes) properties were studied by subcutaneous administration of WX-UK1 to Brown Norwegian (BN) rats carrying orthotopically transplanted BN472 rat breast tumours. WX-UK1 selectively inhibited tumour-related proteases from rats and humans such as uPA, plasmin, or thrombin in the sub or low micromolar range. The activity was stereoselective as the D-enantiomer of WX-UK1 inhibited uPA and plasmin at approximately 70-fold higher Ki values than the active L-form. Chronical administration of the L-enantiomer of WXUK1 impaired primary tumour growth and metastasis of BN472 rat breast cancer in a dose-dependent manner. The minimum inhibitory dosage with maximal effect was between 0.15 and 0.3 mg/kg/day. The inactive D-enatiomer of WX-UK1 was not active in this respect. Daily treatment with WX-UK1 for up to 35 days was well tolerated as judged by the unchanged body and organ weight development. In conclusion, our results provide evidence that WX-UK1 as a single agent inhibits breast tumour growth and metastasis in vivo, and thus is a promising candidate drug to treat human cancer.
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PMID:Suppression of rat breast cancer metastasis and reduction of primary tumour growth by the small synthetic urokinase inhibitor WX-UK1. 1584 27

Plasminogen activator inhibitor-1 (PAI-1) regulates the proteolytic activity of urokinase-type plasminogen activator (uPA) and there is increasing evidence for a PAI-1 role in regulating cell migration/invasion by other mechanisms like vitronectin (VN) binding and lipoprotein-receptor related protein (LRP) binding. We examined the role of PAI-1 to interact with uPA, VN, and LRP in MDA-MB-435 breast cancer and SKOV-3 ovarian cancer cells in a wound-induced cell migration assay. By different experimental conditions with PAI-1, expressed either by stable transfection or by adenoviral infection (wild-type PAI-1 and an inactive reactive site P14 mutant, T333R) or by addition of recombinant PAI-1 and various mutants (stable wild-type, P14 T333R, reactive center P1 R346A, reduced VN-binding Q123K, and reduced LRP-binding R76E), we found that the PAI-1-VN interaction was foremost in suppressing wound-induced cell migration. Likewise, a VN-antibody that blocks cell adhesion to VN mimicked the effect of PAI-1 to reduce wound-induced SKOV-3 cell migration. However, manipulation of the endogenous plasminogen activator system (using blocking antibodies to PAI-1 and to uPA) in wound-induced SKOV-3 cell migration demonstrated an important role for uPA inhibition by PAI-1 that was dependent on plasminogen. By contrast, smooth muscle cell wound-induced migration was promoted by exogenously added PAI-1, but this enhancement was dependent on PAI-1 binding to LRP, not binding to VN. These findings contribute to the overall complexity of the role of PAI-1 in regulating cell migration; especially since both VN binding and uPA inhibition are involved in suppressing wound-induced breast and ovarian cancer cell migration.
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PMID:Wound-induced migration of MDA-MB-435 and SKOV-3 cancer cells is regulated by plasminogen activator inhibitor-1. 1607 25

Recent data on prognostic and predictive significance of breast cancer-associated molecular markers are presented and their clinical value in making individual prognosis and choosing adequate therapy is discussed. Markers of tumor proliferation, steroid hormone receptors, factors of epidermal cell growth, plasminogen activators and inhibitors, factors influencing angiogenesis and apoptosis and genome characteristics are considered. It is concluded that only Ki-67, ER, PR and Her-2/neu may be recommended for clinical use.
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PMID:[Prognostic and predictive factors in breast cancer]. 1630 74

Many advanced human tumors including breast cancer overproduce plasmin that is known to promote angiogenesis and metastasis. The mechanism of this effect is poorly understood. Here we report that annexin II, an endothelial co-receptor for tPA (tissue-type plasminogen activator) and plasminogen, was undetectable in normal and hyperplastic ductal epithelial cells and ductal complexes. By contrast, it was consistently expressed in invasive breast cancer and ductal carcinoma in situ (DCIS) indicating its involvement in breast cancer. Using the well established invasive/metastatic MDA-MB231 cell line and the noninvasive/nonmetastatic MCF-7 human breast cancer cell line, we investigated the mechanism by which annexin II regulates breast cancer progression and metastasis. Western and Northern blot analyses demonstrate selective expression of annexin II in MDA-MB231 cells but not in poorly invasive MCF-7 cells suggesting its participation in invasive breast cancer. Since annexin II is a receptor for plasminogen, we tested whether MDA-MB231 cells are capable of producing plasmin in vitro. MDA-MB231 cell membranes induced plasmin generation in a time-dependent manner while those from MCF-7 cells failed to convert plasminogen to plasmin. The generated plasmin is capable of degrading ECM consequently facilitating cell invasion and migration, biological functions required for angiogenesis and metastasis. Plasmin generation and its dependent invasion and migration can be blocked by a monoclonal antibody to annexin II or angiostatin, potent inhibitors of angiogenesis, breast cancer, and metastasis. Our findings indicate that annexin II-dependent localized plasmin generation by human breast cancer cells could contribute to angiogenesis and metastasis. These results suggest that annexin II may be an attractive target for new anti-angiogenic and anti-breast cancer therapies.
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PMID:Angiogenesis-associated protein annexin II in breast cancer: selective expression in invasive breast cancer and contribution to tumor invasion and progression. 1664 92

The transition from ductal carcinoma in situ (DCIS) of the breast to invasive ductal carcinoma is facilitated by proteolytic degradation of basement membrane. The transition can be identified as microinvasive foci in a small proportion of DCIS lesions. We have previously found that MMP-13 is frequently expressed in such foci. To establish whether plasmin-directed proteolysis is likely to be involved in early invasion, we have here studied the expression of urokinase plasminogen activator (uPA) and its receptor (uPAR) in human DCIS lesions with and without microinvasion. uPA mRNA was detected in periductal stromal cells in all of 9 DCIS lesions with microinvasion and in 2 of 9 DCIS lesions without microinvasion by in situ hybridization. The uPA mRNA signal was seen in numerous stromal cells in microinvasive areas together with MMP-13 mRNA expressing cells. Double immunofluorescence analyses, using emission fingerprinting, showed that the uPA expressing stromal cells included both myofibroblasts and macrophages. The early invasive carcinoma cells were negative for uPA. uPAR immunoreactivity was focally upregulated in periductal stromal cells in all of the 9 DCIS lesions with microinvasion and in only 2 of the 9 DCIS lesions without microinvasion. uPAR was seen in both macrophages and myofibroblasts in microinvasive areas, and it was evident that uPA and uPAR colocalized in both fibroblast-like cells and macrophage-like cells. We conclude that periductal macrophages and myofibroblasts are strongly involved in the initial steps of breast cancer invasion by focally upregulating the expression of the plasminogen activation system and MMP-13.
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PMID:Stromal cells associated with early invasive foci in human mammary ductal carcinoma in situ coexpress urokinase and urokinase receptor. 1729 Apr 5

Proteolytic processing of human plasminogen generates potent antiangiogenic peptides such as angiostatin. The plasminogen kringle 5 (K5) domain, which is distinct from angiostatin, possesses potent antiangiogenic properties on its own, which can be exploited in cancer therapy. It has been recently observed that antiangiogenic agents promote leukocyte-vessel wall interaction as part of their antitumor effect. Although we have previously shown that K5 suppresses cancer growth in tumor xenograft models, its modulation of inflammation in experimental mice with intact immune systems is unknown. To determine whether K5 possesses immune proinflammatory properties, we investigated the effects of K5 in an immune competent model of breast cancer and observed that tumor rejection is substantially reduced in nonobese diabetic/severe combined immunodeficient and BALB/c nude when compared with wild-type BALB/c mice, suggesting an important role for T-lymphoid cells in the antitumor effect of K5. Tumor explant analysis shows that K5 enhances tumor recruitment of CD3(+) lymphoid cells, in particular, the NKT phenotype. We also observed a significant decrease in tumor-associated microvessel length and density consistent with antiangiogenic activity. Histologic analysis of K5 tumors also revealed a robust neutrophilic infiltrate, which may be explained by the neutrophil chemotactic activity of K5 as well as its ability to promote CD64 up-regulation within the CD11b(+) adhesive neutrophil population. In sum, our findings confirm that the K5 protein acts as a potent angiostatic agent and possesses a novel proinflammatory role via its ability to recruit tumor-associated neutrophils and NKT lymphocytes, leading to a potent antitumor response.
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PMID:Plasminogen Kringle 5 blocks tumor progression by antiangiogenic and proinflammatory pathways. 1730 45

Extracellular matrix degradation, mediated by the urokinase plasminogen activation (uPA) system, is a critical step in tumor invasion and metastasis. High tumor levels of uPA and its inhibitor PAI-1 have been correlated with poor prognosis in breast cancer. We examined whether genetic variation in the genes of the uPA system affect breast cancer susceptibility and prognosis. We genotyped eight potentially functional single nucleotide polymorphisms (SNPs) in six genes of the uPA system in 959 Swedish breast cancer patients with detailed clinical data and up to 15 years of follow-up together with 952 matched controls. We used the unconditional logistic regression models to evaluate the associations between genotypes and breast cancer risk and tumor characteristics. The Kaplan-Meier method was used to estimate the survival probabilities; the log-rank test was used to test differences between subgroups. None of the SNPs conferred an increased breast cancer risk, but correlation with some traditional prognostic factors was observed for several SNPs. Most importantly, we identified the -675 4G/5G SNP in the PAI-1 gene as a promising prognostic biomarker for breast cancer. Compared to the 4G/4G and 4G/5G genotypes 5G/5G homozygosity correlated significantly with worse survival (RR 2.04, 95% CI 1.45-2.86, P<0.001), especially in patients with more aggressive tumors. 5G/5G homozygotes were also the group with worse survival among lymph node negative cases. Our finding suggests that genotyping PAI-1 -675 4G/5G may help in clinical prognosis of breast cancer.
Breast Cancer Res Treat 2008 May
PMID:PAI-1 -675 4G/5G polymorphism as a prognostic biomarker in breast cancer. 1761 7

PAI-1 and PAI-2 (plasminogen-activator inibitor types 1 and 2) are inhibitors of cell surface uPA (urokinase plasminogen activator). However, tumour expression of PAI-1 and PAI-2 correlates with poor compared with good patient prognosis in breast cancer respectively. This biological divergence may be related to additional functional roles of PAI-1. For example, the inhibition of uPA by PAI-1 reveals a cryptic high-affinity site within the PAI-1 moiety for the VLDLr (very-low-density-lipoprotein receptor), which sustains cell signalling events initiated by binding of uPA to its receptor. These interactions and subsequent signalling events promote proliferation of breast cancer cells. Biochemical and structural analyses show that, unlike PAI-1, the PAI-2 moiety of uPA-PAI-2 does not contain a high-affinity-binding site for VLDLr, although uPA-PAI-2 is still efficiently endocytosed via this receptor in breast cancer cells. Furthermore, global protein tyrosine phosphorylation events were not sustained by uPA-PAI-2 and cell proliferation was not affected. We thus propose a structurally based mechanism for these differences between PAI-1 and PAI-2 and suggest that PAI-2 is able to inhibit and clear uPA activity without initiating mitogenic signalling events through VLDLr.
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PMID:A structural basis for differential cell signalling by PAI-1 and PAI-2 in breast cancer cells. 1769 82

Novel inhibitors of the urokinase-mediated plasminogen (plg) activation system are potentially of great clinical benefit as anticancer treatments. Using phage display, we identified DX-1000 a tissue factor pathway inhibitor-derived Kunitz domain protein which is a specific high-affinity inhibitor of plasmin (pln) (K(i) = 99 pM). When tested in vitro, DX-1000 blocks plasmin-mediated pro-matrix metalloproteinase-9 (proMMP-9) activation on cells and dose-dependently inhibits tube formation, while not significantly affecting hemostasis and coagulation. However, this low-molecular weight protein inhibitor ( approximately 7 kDa) exhibits rapid plasma clearance in mice and rabbits, limiting its potential clinical use in chronic diseases. After site-specific PEGylation, DX-1000 retains its activity and exhibits a decreased plasma clearance. This PEGylated derivative is effective in vitro, as well as potent in inhibiting tumor growth of green fluorescent protein (GFP)-labeled MDA-MB-231 cells. 4PEG-DX-1000 treatment causes a significant reduction of urokinase-type plasminogen activator (uPA) and plasminogen expressions, a reduction of tumor proliferation, and vascularization. 4PEG-DX-1000 treatment significantly decreases the level of active mitogen-activated protein kinase (MAPK) in the primary tumors and reduces metastasis incidence. Together, our results demonstrate the potential value of plasmin inhibitors as therapeutic agents for blocking breast cancer growth and metastasis.
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PMID:PEGylated DX-1000: pharmacokinetics and antineoplastic activity of a specific plasmin inhibitor. 1803 Mar 61


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