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)

To evaluate the prognostic relevance of Ki-67 and topoisomerase IIalpha expression in relation to tumor stage, grade, and hormone receptor content, 942 ductal infiltrating carcinomas of the breast were examined by means of the monoclonal antibodies Ki-S11 (Ki-67) and Ki-S4 (topoisomerase IIalpha). pS2, c-erbB2, and p53 were additionally considered as prognostic variables. The median follow-up time was 149 months. Eight-hundred-and-sixty-three tumors reacted with Ki-S11 and Ki-S4; the labeling indices of the two antigens were closely associated (r = 0.93). Both correlated positively with the tumor size, c-erbB2, and p53 expression, and negatively with patient age, hormone receptor content, and pS2 immunostaining. In the univariate analysis, Ki-S11 and Ki-S4 scores, nodal status, tumor size, tumor grade, and progesterone receptor content strongly predicted both overall and metastasis-free survival (p < 0.00001). Estrogen receptor status, p53, and c-erbB2 were of minor significance. Concerning overall survival, multivariate Cox regression analysis selected a Ki-S4 score >25% (p < 0.00001) next to the nodal status, and before tumor size, progesterone receptor content, and patient age. Independent predictors of the occurrence of distant metastases were nodal status, Ki-S4, tumor size, grade 1, and progesterone receptor negativity, in that order. The Ki-S11 score was of independent prognostic significance only if examined as a continuous variable. We conclude that topoisomerase IIalpha expression as assessed by monoclonal antibody Ki-S4 may add valuable information to current prognostic models for breast cancer. Its predictive value appears to be essentially related to the proliferative activity of tumor cells.
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PMID:Prognostic significance of Ki-67 and topoisomerase IIalpha expression in infiltrating ductal carcinoma of the breast. A multivariate analysis of 863 cases. 1047 80

pS2 was measured by radioimmunometric assay in tumour extracts from 197 breast cancer patients. Values ranged from 0 to 50 ng/mg protein (mean 9.6 and median 3 ng/mg). We found no correlation with age, menopausal status, nodal metastases, disease stage or tumour histology. There was, however, a linear relationship with both ER (p < 0.0001) (particularly nuclear ER) and PR (p < 0.0001) expression determined by enzyme immunoassay (ELISA), as well as a good correlation when high and low expressors were stratified on the basis of combined ER/PR expression using consensus cut-off points. Only 15% of ER - ve/PR - ve patients were classified as pS2 + ve compared with 83% of those who were ER + ve/PR + ve. pS2 was also directly correlated with high expression of tPA and inversely with uPA. Comparison with previous studies showed that the current ELISA method produced consistent results, in contrast to other methods, particularly those based on immunohistochemical detection. The close relationship between pS2 and both steroid receptors suggests that pS2 may be important in terms of defining hormone-responsive patients who are likely to benefit from endocrine therapy.
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PMID:Immunoradiometric measurement of pS2 in breast cancer--correlation with steroid receptors and plasminogen activators. 1052 72

The spread of cancer cells to regional lymph nodes through the lymphatic system is the first step in the dissemination of breast cancer. In several human cancers including those of the breast and prostate, the expression of vascular endothelial growth factor C (VEGF-C) is associated with lymph node metastasis. Our study was undertaken to evaluate the effect of VEGF-C on metastasis of poorly invasive, estrogen dependent human MCF-7 breast cancer cells. MCF-7 breast cancer cells transfected with VEGF-C (MCF-7-VEGF-C) were grown as tumors in the mammary fat pads of nude mice implanted with subcutaneous estrogen pellets. Tumor lymphangiogenesis and lymph node metastasis were studied immunohistochemically using antibodies against lymphatic vessel hyaluronan receptor -1 (LYVE-1), VEGF receptor-3 (VEGFR-3), PECAM-1, pan-cytokeratin and estrogen dependent pS2 protein. Overexpression of VEGF-C in transfected MCF-7 cells stimulated in vivo tumor growth in xenotransplanted mice without affecting estrogen responsiveness. The resulting tumors metastasized to the regional lymph nodes in 75% (in 6 mice out of 8, Experiment I) and in 62% (in 5 mice out of 8, Experiment II) of mice bearing orthotopic tumors formed by MCF-7-VEGF-C cells whereas no metastases were observed in mice bearing tumors of control vector-transfected MCF-7 cells (MCF-7-Mock). The density of intratumoral and peritumoral lymphatic vessels was increased in tumors derived from MCF-7-VEGF-C cells but not MCF-7-Mock cells. Taken together, our results show that VEGF-C overexpression stimulates tumor lymphangiogenesis and induces normally poorly metastatic estrogen-dependent MCF-7 tumors to disseminate to local lymph nodes. These data suggest that VEGF-C has an important role in lymph node metastasis of breast cancer even at its hormone-dependent early stage.
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PMID:VEGF-C induced lymphangiogenesis is associated with lymph node metastasis in orthotopic MCF-7 tumors. 1194 78

Although the expression of the metastases-associated gene MTA1 correlates with tumor metastases, its role in regulating type IV collagenase expression is unknown. Enforced MTA1 expression in HT1080 cells reduced basal and 12-myristate 13-acetate-induced 92-kDa type IV collagenase (MMP-9) protein/mRNA levels. DNase I hypersensitivity and PstI accessibility assays revealed multiple regions of the MMP-9 promoter (-650/-450 and -120/+1), showing reduced hypersensitivity in the MTA1-expressing cells. Chromatin immunoprecipitation assays demonstrated MTA1 binding to the distal region, which spans several regulatory cis elements. Co-immunoprecipitation and chromatin immunoprecipitation assay experiments revealed histone deacetylase 2 (HDAC2)-MTA1 protein-protein interactions and the MTA1-dependent recruitment of HDAC2 to the distal MMP-9 promoter region, yielding diminished histone H3/H4 acetylation. However, HDAC2 binding and H3/H4 acetylation at the proximal MMP-9 region were unaffected by MTA1 expression. Furthermore, trichostatin treatment only partially relieved MTA1-repressed MMP-9 expression, indicating a HDAC-insensitive component possibly involv ing the nucleosome-remodeling Mi2 activity, which was recruited to the promoter by MTA1. In summary, (a) MMP-9 adds to a short list of MTA1-regulated genes, which so far only includes c-myc and pS2, and (b) MTA1 binds to the MMP-9 promoter, thereby repressing expression of this type IV collagenase via histone-dependent and independent mechanisms.
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PMID:Repression of 92-kDa type IV collagenase expression by MTA1 is mediated through direct interactions with the promoter via a mechanism, which is both dependent on and independent of histone deacetylation. 1243 81

We conducted an analysis on 41 cases of male breast cancer (median age 54 y; range 25-82 y) in Kuwait. Most (51%) were stage II cancers with 65% arising in the left breast. There were 5 (12%) T1 tumours, 23 (56%) T2 tumours and 13 (32%) T3/T4 tumours. They were mostly (95%) infiltrating ductal carcinomas; 97% were grade 2 or 3. Axillary lymph node involvement was found in 69%. Estimated 5-year survival rates were 67% and 58% for overall and relapse free survival respectively. Favourable prognosis was associated with age below 50y, clinical stage I and II, small tumour size (T1, T2), low tumour grade and absence of nodal involvement or distant metastases; nodal status and grade were independent factors for relapse free survival in multivariate analysis. In 18 cases, an immunohistochemical study showed some degree of tumour antigen reaction for ER in 89% of cases, PR in 61%, pS2 in 44%, CathD in 72%, p53 in 56%, c-erbB-2 in 50%, Ki67 and PCNA in 100% and bcl-2 in 78%. There were significant associations between several of these factors but none influenced survival. Despite the high incidence of staining of ER, our data do not support the concept of an endocrine pathway that could be usefully antagonized with antioestrogens for therapeutic benefit, as in women.
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PMID:Evaluation of prognostic factors in male breast cancer. 1496 80

Trefoil factor family protein 1 (TFF1, pS2) interacts with mucins to protect gastrointestinal epithelium against injury and contributes to mucosal repair by promoting epithelial cell migration and restitution. Moreover, TFF1 has antiproliferative and anti-apoptotic effects and promotes cell scattering and invasion. We investigated TFF1 expression in healthy and inflamed non-neoplastic gallbladder mucosa as well as in gallbladder carcinomas (n=57) and corresponding metastases (n=18), using a tissue microarray technique. TFF1 immunoreactivity was absent in healthy mucosa, focally observed in epithelium with inflammatory changes and present in 35% of primary and 24% of metastatic cancer tissues. Immunoreactivity significantly decreased with increasing tumour stage (P=0.009) and increasing tumour grade (P=0.001). Patients with TFF1 positive tumours showed a more favourable outcome compared to patients with TFF1 negative tumours in univariate analysis (P=0.006). However, multivariate analysis proved resection status and tumour grade as the only independent prognostic factors. In conclusion, TFF1 is expressed in inflamed non-neoplastic gallbladder epithelium and in low stage and low grade gallbladder carcinomas. Thus, TFF1 may be the missing link between gallstones, chronic cholecystitis and gallbladder cancer. Further studies are needed to evaluate whether TFF1 immunostaining can be used as a diagnostic tool to identify patients with a more favourable outcome.
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PMID:Analysis of trefoil factor family protein 1 (TFF1, pS2) expression in chronic cholecystitis and gallbladder carcinoma. 1582 28

There is increasing evidence that molecular detection of micrometastatic breast cancer in the axillary lymph nodes (ALN) of breast cancer patients can improve staging. Molecular analyses of samples obtained from the Minimally Invasive Molecular Staging of Breast Cancer Trial (n = 489 patients) indicate that whereas the majority of molecular markers are informative for the detection of metastatic breast cancer (significant disease burden), only a few are sensitive for the detection of micrometastatic disease (limited disease burden). Frequency distribution and linear regression analyses reveal that relative levels of gene expression are highly correlated with apparent sensitivity for the detection of micrometastic breast cancer (P < 0.05). These data provides statistical validation of the concept that the most informative markers for detection of micrometastatic disease are those that are most highly expressed in metastatic disease. To test this hypothesis, we developed an innovative microarray strategy. RNA from a metastatic breast cancer ALN was diluted into RNA from a normal lymph node and analyzed using Affymetrix microarrays. Expression analysis indicated that only two genes [mammaglobin (mam) and trefoil factor 1 (TFF1)] were significantly overexpressed at a dilution of 1:50. Real-time reverse transcription-PCR analysis of pathology-negative ALN (n = 72) confirm that of all the markers tested, mam and TFF1 have the highest apparent sensitivity for detection of micrometastatic breast cancer. We conclude that a dilutional microarray approach is a simple and reliable method for the identification of informative molecular markers for the detection of micrometastatic cancer.
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PMID:An innovative microarray strategy identities informative molecular markers for the detection of micrometastatic breast cancer. 1620 99

Colorectal carcinoma shows several sex-related differences with regard to incidence, response to chemotherapy and microsatellite instability. These differences may relate to differential expression of ERbeta1 (wild-type) as well as the truncated ERbeta2 and ERbeta5 splice variant isoforms, which have recently been detected in normal and malignant colorectal epithelium. This hypothesis was tested through the study of ERbeta isoform protein and/or mRNA expression amongst 91 primary colorectal carcinoma cases and 20 colorectal carcinoma cell lines. Study of the latter showed an absolute correlation between mRNA and protein expressions for ERbeta1 and ERbeta2. ERbeta1 and ERbeta2 protein expression was lost in 22% and 49%, respectively, of the primary colorectal carcinomas. By contrast, ERbeta5 expression was found in all primary colorectal carcinomas and all colorectal carcinoma cell lines studied. Lower ERbeta1 protein expression was associated with poorer differentiation, higher pT stage and absence of microsatellite instability. Higher ERbeta2 protein expression was associated with right-sided location and presence of lymph node metastases. Protein expression of ERbeta1 correlated positively with expression of the oestrogen-responsive protein trefoil factor 1 (TFF1). There was no correlation between ERbeta protein isoform expression and response to 5-fluorouracil therapy, tumour proliferation, or thymidylate synthase expression. These data suggest that ERbeta1 and/or ERbeta2 isoform expression may have prognostic value and may explain sex-related differences in microsatellite instability and colorectal carcinoma. The opposing associations shown by ERbeta1 and/or ERbeta2 in relation to colorectal carcinoma are in keeping with differential activities shown by the two isoforms.
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PMID:ERbeta isoform expression in colorectal carcinoma: an in vivo and in vitro study of clinicopathological and molecular correlates. 1595 65

The development of distant metastases is the major cause of death from breast cancer. In order to predict and prevent tumour spreading, many attempts are being made to detect small numbers of tumour cells that have shed from the primary lesions and have moved to lymph nodes, blood or bone marrow. This article presents the advantages and the limitations of techniques used for disseminated tumour cells (DTC) detection. DTC markers are listed and the most currently used of them (KRT19, CEACAM5, TACSTD1, MUC1, EGFR, ERBB2, SCGB2A2, SCGB2A1, SCGB1D2, PIP, SBEM, TFF1, TFF3, ANKRD30A, SPDEF, ESR1, SERPINB5 and GABRP) are discussed, notably on the basis of recent data on breast tumour portraits (luminal epithelial-like, basal/myoepithelial-like and ERBB2). The significance of DTC for the prognosis and prediction of response to therapy is examined. DTC viability, the notion of cell dormancy and the concept of breast cancer stem cells are also discussed.
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PMID:Significance, detection and markers of disseminated breast cancer cells. 1715 53

Metastasis of cancer cells from the primary tumor is associated with poor prognosis and decreased overall survival. One protein implicated in inhibiting metastasis is the tumor metastasis suppressor nonmetastatic protein 23 homologue 1 (NM23-H1). NM23-H1 is a multifunctional protein, which, in addition to limiting metastasis, has DNase and histidine protein kinase activities. We have identified new functions for NM23-H1 in influencing estrogen receptor alpha (ER alpha)-mediated gene expression. Using a battery of molecular and biochemical techniques, we show that NM23-H1 interacts with ER alpha and increases the ER alpha-estrogen response element (ERE) interaction. When NM23-H1 expression is increased in U2 osteosarcoma and MDA-MB-231 breast cancer cells, transcription of a transiently transfected, estrogen-responsive reporter plasmid is decreased. More importantly, when endogenous NM23-H1 expression is knocked down in MCF-7 human breast cancer cells using small interfering RNA, estrogen responsiveness of the progesterone receptor (PR), Bcl-2, cathepsin D, and cyclin D1 genes, but not the pS2 gene, is enhanced. Furthermore, NM23-H1 associates with the region of the PR gene containing the +90 activator protein 1 site, but not with the ERE-containing region of the pS2 gene, indicating that NM23-H1 mediates gene-specific effects by association with endogenous chromatin. Our studies suggest that the capacity of NM23-H1 to limit the expression of estrogen-responsive genes such as cathepsin D and Bcl-2, which are involved in cell migration, apoptosis, and angiogenesis, may help to explain the metastasis-suppressive effects of this protein. The complementary abilities of ER alpha and NM23-H1 together to influence gene expression, cell migration, and apoptosis could be key factors in helping to determine tumor cell fate.
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PMID:Interaction of the tumor metastasis suppressor nonmetastatic protein 23 homologue H1 and estrogen receptor alpha alters estrogen-responsive gene expression. 1797 5


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