Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The study of several human breast cancer cell lines containing oestrogen receptors has allowed characterization of a number of oestrogen-induced proteins (e.g. progesterone receptor, cathepsin D, pS2, Hsp27, c-Myc). In primary tumours these markers have different prognostic significance for predicting whether the tumour will be hormone responsive (e.g. pS2, progesterone receptor) and whether it will metastasize (e.g. cathepsin D). The mechanism of regulation of gene expression by oestrogens and anti-oestrogens in breast cancer is complex and varies according to the nature of both the gene and the cell in which it is transcribed. Our laboratory has identified the sequences mediating oestrogen activity in the proximal region of cathepsin D, including a non-consensus oestrogen-responsive element located at -260 which acts in synergy with other regulatory elements. In addition to the classical effect of oestrogen receptor in stimulating transcription of genes controlled by the oestrogen-responsive element, we found that estrogen receptor is able to modulate transcription of AP-1-responsive genes without interacting directly with DNA. Cross-talk between oestrogen receptor and members of the Fos/Jun family via protein-protein interactions may explain how anti-oestrogens inhibit the mitogenic effect of growth factors in the apparent absence of oestrogens and why tamoxifen is able to stimulate cathepsin D gene expression and induce apoptosis in certain oestrogen receptor-positive breast cancer cells. The nature and degree of this cross-talk appears to vary according to the gene, the cell type and the type of oestrogen receptor ligand involved. Studies of oestrogen-regulated genes are not only useful for classifying breast cancers according to their ability to metastasize and respond to therapies, but also should lead to new therapeutic approaches for hormone-dependent and hormone-resistant cancers.
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PMID:Oestrogen- and anti-oestrogen-regulated genes in human breast cancer. 858 2

Overexpression of the proto-oncogene c-myc has been associated with neoplastic transformation in a variety of tumors. For human melanoma high c-myc expression has been found in the vertical growth phase and higher positivity reported in metastases than primary tumors. The principle aim of this study was to determine, whether c-Myc expression influences the metastatic behavior of human melanoma in the absence of lymphocyte-mediated immune phenomena. The growth characteristics and tumor biology of two c-myc transfectants of the human melanoma cell line IGR39D, expressing c-Myc 1.7 and three times over baseline and the respective vector control were analyzed both in vitro and in a severe combined immunodeficient mouse model in vivo. Both c-myc transfectants showed increased growth rates, anchorage independent growth and directed cell movement in culture. Subcutaneously implanted IGR39D melanomas highly overexpressing c-Myc spontaneously formed macroscopic metastases (lymph nodes and lung) in severe combined immunodeficient mice in all cases (n = 7 per group), whereas less prominent c-Myc overexpression caused the development of only lung micrometastases. During the time period leading to terminal disease in animals injected with c-myc transfected human melanoma cells, melanoma development was not seen in vector controls. These findings suggest that constitutive high c-Myc expression in human melanoma results in a more aggressive growth behavior both in vitro and in vivo and favors metastasis in severe combined immunodeficient mice by factors unrelated to immune phenomena such as class I human leukocyte antigen downregulation known to be associated with c-Myc expression.
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PMID:Influence of increased c-Myc expression on the growth characteristics of human melanoma. 1008 11

We have examined whether the extended life span of cells induced by Bcl-2 in T(1) ductal breast carcinomas might favor the acquisition and accumulation of genetic alterations that induce lymph node metastases. We analyzed the expression of c-Myc, c-erbB-2 and epidermal growth factor receptor by immuno-histochemistry in a group of 142 T(1) (<2 cm) ductal breast carcinomas embedded in paraffin, previously studied for p53 mutation and Bcl-2 over-expression. We also measured the apoptotic status and estimated the excess risk (pOR) for lymph node metastasis according to the number of accumulated oncogene alterations and Bcl-2 and p53 expression. The linear relationship between number of oncogene alterations and presence of lymph node metastasis was statistically significant in Bcl-2-positive tumors (trend test, p = 0.03), p53-mutated tumors (trend test, p = 0.08) and tumors with loss of apoptosis (trend test, p = 0.08). Very large associations (pOR > 12) between the number of oncogene alterations and lymph node metastasis were observed among Bcl-2-positive tumors that showed increased loss of apoptosis (trend test, p = 0.03). Furthermore, in p53-negative tumors, a strong linear association was found between the number of oncogene alterations and risk of lymph node metastasis among Bcl-2-positive tumors (trend test, p = 0.03). In human T(1) ductal breast carcinoma, over-expression of Bcl-2 along with loss of apoptosis might render breast cancer cells susceptible to the acquisition of additional genetic lesions related to disease progression among p53-negative tumors. Thus, in breast cancer, there are at least 2 pathways to progression: Bcl-2- and p53-dependent mechanisms.
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PMID:Bcl-2 with loss of apoptosis allows accumulation of genetic alterations: a pathway to metastatic progression in human breast cancer. 1075 91

The HMG-I gene family encodes high mobility group proteins originally identified as nonhistone chromosomal binding proteins. HMG-I and -Y proteins are alternatively spliced products of the same mRNA; HMG-C is encoded by a separate gene. The HMG-I proteins function as architectural chromatin-binding proteins that bind to the narrow groove of AT-rich regions in double-stranded DNA. Recent studies indicate an important role for HMG-I proteins in regulating gene expression. Moreover, increased expression of the HMG-I, -Y, and -C proteins correlates with cellular proliferation and neoplastic transformation in several cell types and human cancers. Previous work from our laboratory has shown that HMG-I is a direct c-Myc target gene that is involved in Myc-mediated neoplastic transformation. In this report, we show that increased expression of HMG-Y or -C leads to transformation with anchorage-independent cell growth in two experimental cell lines in a manner similar to that of HMG-I or c-Myc. Moreover, Rat la cells overexpressing HMG-Y or -C form tumors in nude mice analogous to Rat 1a cells overexpressing HMG-I or c-Myc. Distant metastases developed in animals injected with cells overexpressing HMG-I or -C. Our findings suggest that the HMG-I gene family is involved in neoplastic transformation and may represent a new family of oncogenes important in the pathogenesis of several human cancers.
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PMID:The oncogenic properties of the HMG-I gene family. 1094 39

Increased expression and/or activity of c-Met, the receptor protein tyrosine kinase for hepatocyte growth factor/scatter factor, occurs commonly during colon tumor progression. To examine potential roles for c-Met in promoting metastasis, we compared the colon tumor cell line KM12C with low metastatic potential to the isogenic variants KM,12L4 and KM12SM with high metastatic potential. KM12C cells express c-Met with low levels of tyrosine phosphorylation in the absence of HGF. The high metastatic cells express a c-Met that is constitutively tyrosine phosphorylated, they have increased colony formation, and are minimally responsive to HGF relative to the parental cells. Tyrosine-phosphorylated beta-catenin was constitutively associated with c-Met in the more metastatic cells, but was inducible only after HGF addition in the less metastatic cells. Functions mediated by beta-catenin, including cell-cell adhesion and migration, and activation of the tcf (T-cell factor) family of transcription factors, were also elevated in the more metastatic KM12SM and L4 cells. Furthermore, analysis of the known tcf transcriptional target genes, cyclin D1, c-Myc, and uPAR, demonstrated increased expression in the high metastatic cells, correlating with the levels of tcf activity. Collectively, these results suggest that endogenous activation of c-Met in highly metastatic KM12SM CRC cells results in increased survival and growth under anchorage independent conditions, increased in vitro migration, and elevated levels of tcf target genes. Thus, beta-catenin association with activated c-Met may contribute to a more aggressive liver metastatic phenotype of these cells.
Clin Exp Metastasis 2003
PMID:Activation of c-Met in colorectal carcinoma cells leads to constitutive association of tyrosine-phosphorylated beta-catenin. 1285 16

Non-membranous beta-catenin and gamma-catenin, c-Myc and cyclin D1 are key participants in the Wnt cell signalling pathway, in which aberrancies have been associated with malignant cell transformation. We assessed the independent prognostic value of these proteins in a clinical material. Tumours from a series of 162 patients operated on for Dukes' stage A, B and C colonic adenocarcinomas were analysed using semiquantitative immunohistochemistry and the results were related to patient outcome. Patients expressing nuclear beta-catenin in the primary tumour showed reduced survival compared to other patients (log rank p=0.028) and there was also an association with development of metastases follow-up (logistic regression p=0.024). Using multivariate analysis (Cox regression) co-expression of nuclear beta-catenin and c-Myc turned out to be the strongest marker of impaired prognosis (p=0.001, HR 5.26, 95% CI 1.93-14.36). Expression of non-membranous gamma-catenin, cyclin D1 and c-Myc alone failed to have independent prognostic significance in our study.
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PMID:Expression of non-membranous beta-catenin and gamma-catenin, c-Myc and cyclin D1 in relation to patient outcome in human colon adenocarcinomas. 1496 75

Transitional cell carcinoma of the bladder is a common tumor. While most patients presenting superficial disease can be expected to do well following treatment, still many patients will return to our office with muscle invasive and metastatic disease. Survival in advanced bladder cancer is less than 50%. Tumors of similar histologic grade and stage have variable behavior, suggesting that genetic alterations must be present to explain the diverse behavior of bladder cancer. It is hoped that through the study of the subtle genetic alterations in bladder cancer, important prognostic and therapeutic targets can be exploited. Many new diagnostic tests and gene therapy approaches rely on the identification and targeting of these unique genetic alterations. A review of literature published on the molecular genetics of bladder cancer from 1970 to the present was conducted. A variety of molecular genetic alterations have been identified in bladder cancer. Oncogenes (H-ras, erbB-2, EGFR, MDM2, C-MYC, CCND1), tumor suppressor genes (p53, Rb, p21, p27/KIP1, p16, PTEN, STK15, FHIT, FEZ1/LZTS1, bc10), telomerase, and methylation have all been studied in bladder cancer. Several have proven to be potentially useful clinical targets in the prognosis and therapy of bladder cancer such as staining for p53 and gene therapy strategies such as p53 and fez1. Clinical trials targeting HER2/neu and the EGFR pathways are underway. The UroVysion bladder cancer assay relies on FISH to detect genetic alterations in this disease. Continuing identification of the molecular genetic alterations in bladder cancer will enhance future diagnostic and therapeutic approaches to bladder cancer. Capitalizing on these alterations will allow early detection, providing important prognostic information and unique targets for gene therapy and other therapeutic approaches.
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PMID:Molecular genetics of bladder cancer: targets for diagnosis and therapy. 1691 24

Inflammatory myofibroblastic tumor (IMT) is a neoplasm of intermediate biologic potential. In this study, we report a subset of IMTs with histologic atypia and/or clinical aggressiveness that were analyzed for clinicopathologic features, outcome, and immunohistochemical expression of anaplastic lymphoma kinase (ALK) and other markers to identify potential pathologic prognostic features. Fifty-nine IMTs with classic morphology (5 cases), atypical histologic features (21 cases), local recurrence (27 cases), and/or metastasis (6 cases) were studied. Immunohistochemistry was performed for ALK1 and other markers (Mib-1, c-Myc, cyclin D1, caspase 3, Bcl-2, Mcl-1, survivin, p27, CD56, p53, MDM-2) using standard techniques. The 59 IMTs had an age at diagnosis ranging from 3 weeks to 74 years (mean 13.2 y, median 11 y, 44% in the first decade). The mean tumor size was 7.8 cm. Sites included the abdomen or pelvis in 64%, lung in 22%, head and neck in 8%, and extremities in 5%. The follow-up ranged from 3 months to 11 years, with a mean of 3.6 years and a median of 3 years. Thirty-three patients had local recurrences, including 13 with multiple local recurrences and 6 patients with both local recurrences and distant metastases. Six patients died of disease, 5 with local recurrences, and 1 with distant metastases. Histologic evolution to a more pleomorphic cellular, spindled, polygonal, or round cell morphologic pattern was observed in 7 cases. Abdominal and pelvic IMTs had a recurrence rate of 85%. Recurrent and metastatic IMTs were larger, with mean diameters of 8.7 and 11 cm, respectively. Cytoplasmic ALK reactivity was seen in 56%. ALK-negative IMTs occurred in older patients (mean age 20.1) years and had greater nuclear pleomorphism, atypia, and atypical mitoses. All 6 metastatic IMTs were ALK-negative. Nuclear expression of p53 was detected in 80% of IMTs overall, but in only 25% of the metastatic subset. There were no significant differences among the subgroups for c-Myc, cyclin D1, MDM-2, Mcl-1, Bcl-2, CD56, p27, caspase 3, or survivin expression. In conclusion, among these 59 IMTs, ALK reactivity was associated with local recurrence, but not distant metastasis, which was confined to ALK-negative lesions. Absent ALK expression was associated with a higher age overall, subtle histologic differences, and death from disease or distant metastases (in a younger subset). Other proliferative, apoptotic, and prognostic markers did not correlate well with morphology or outcome. Thus, ALK reactivity may be a favorable prognostic indicator in IMT and abdominopelvic IMTs recur more frequently.
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PMID:Inflammatory myofibroblastic tumor: comparison of clinicopathologic, histologic, and immunohistochemical features including ALK expression in atypical and aggressive cases. 1741 97

Deregulation of beta-catenin signaling is an important event in the genesis of several human malignancies including prostate cancer. We investigated the effects of apigenin, a naturally occurring plant flavone, on prostate carcinogenesis in TRAMP mice and further elucidated its mechanism of action. Oral intake of apigenin by gavage at doses of 20 and 50 microg/mouse/d, 6 days per week for 20 weeks, significantly decreased tumor volumes of the prostate as well as completely abolished distant-site metastases to lymph nodes, lungs, and liver in TRAMP mice. Apigenin-treated mice had significantly diminished weights of their genitourinary apparatuses and dorsolateral and ventral prostate lobes, compared with the control group, and showed reduced proliferation and increased apoptosis in the dorsolateral prostates, which correlated with elevated plasma apigenin levels. Continuous intake of apigenin up to 50 weeks by TRAMP mice significantly improved their overall survival. P.o. administration of apigenin further resulted in increased levels of E-cadherin and decreased levels of nuclear beta-catenin, c-Myc, and cyclin D1 in the dorsolateral prostates of TRAMP mice. Similar effects were noted in TRAMP mice with established tumors. Treatment of DU145 human prostate cancer cells with 10 and 20 micromol/L apigenin also increased protein levels of E-cadherin by 27% to 74%, inhibited nuclear translocation of beta-catenin and its retention in the cytoplasm, and decreased c-Myc and cyclin D1 levels, an effect similar to the exposure of cells to beta-catenin small interfering RNA. Our results indicate that apigenin effectively suppressed prostate carcinogenesis in TRAMP mice, at least in part, by blocking beta-catenin signaling.
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PMID:Blockade of beta-catenin signaling by plant flavonoid apigenin suppresses prostate carcinogenesis in TRAMP mice. 1763 4

Loss or inhibition of the serine/threonine protein phosphatase 2A (PP2A) has revealed a critical tumor suppressor function for PP2A. However, PP2A has also been shown to have important roles in cell cycle progression and survival. Therefore, PP2A is not a typical tumor suppressor. This is most likely due to the fact that PP2A represents a large number of different holoenzymes. Further understanding of PP2A function(s), and especially its tumor suppressor activity, will depend largely on our ability to determine specific targets for these different PP2A holoenzymes and to gain an understanding of how these targets confer tumor suppressor activity or contribute to cell cycle progression and cell survival. Recent work has identified c-Myc as a target of the PP2A holoenzyme, PP2A-B56alpha. This holoenzyme also negatively regulates beta-catenin expression and modulates the anti-apoptotic activity of Bcl2, thus characterizing PP2A-B56alpha as a tumor suppressor PP2A holoenzyme. This review will focus on the role of PP2A-B56alpha in regulating c-Myc and will place this tumor suppressor activity of PP2A within the context of its other tumor suppressor functions. Finally, the mechanism(s) through which PP2A-B56alpha tumor suppressor activity may be lost in cancer will be discussed.
Cancer Metastasis Rev 2008 Jun
PMID:A tumor suppressor role for PP2A-B56alpha through negative regulation of c-Myc and other key oncoproteins. 1824 11


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