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)

The murine 18A2/mts1 and its human homolog h-mts1 (S100A4), encoding a Ca2+-binding protein belonging to the S-100 family, are associated with high invasive and metastatic potentials of murine tumors, human tumor cell lines in vitro, and human tumors growing as xenografts. The nm23 is a putative metastasis-suppressor gene whose expression has been found to correlate inversely with the metastatic potential of some forms of human cancer. The products of both human genes alter cytoskeletal dynamics, with antagonistic effects. In view of the equivocal association of nm23 with the metastatic potential of human cancer, we suspected that the relative expression of h-mts1 and nm23 might reflect tumor progression more accurately than either of them alone. We describe here the expression of these genes in infiltrating ductal carcinomas of the breast and show that high h-mts1 expression is associated with metastatic spread to the regional lymph nodes. The expression of nm23 on its own did not show a statistically significant inverse correlation with nodal spread. However, the expression status of the two genes, taken together, correlated strongly with the occurrence of nodal metastases. Breast cancers with no detectable expression of h-mts1 were found to be estrogen and progesterone receptor positive. Expression of h-mts1 was not related to tumor differentiation. The clinical data, together with the state of expression of steroid receptors and the expression levels of h-mts1 and nm23 genes, were analyzed using artificial neural networks for accuracy in predicting nodal spread of the carcinomas. These analyses support the conclusion that, overall, h-mts1 expression appears to be associated with and indicative of more aggressive disease. Complemented with nm23, h-mts1 could provide a powerful marker of breast cancer prognosis.
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PMID:Expression of metastasis-associated genes h-mts1 (S100A4) and nm23 in carcinoma of breast is related to disease progression. 957 Jan 50

Cancer is a genetic disease resulting from an accumulation of genetic abnormalities in various regulatory genes. Most studies on genetic alterations in human breast cancer have involved primary tumors. The possible involvement of specific tumor suppressor genes in the later stages of cancer progression is poorly documented. We investigated allelic losses associated with breast cancer progression by analyzing 55 polymorphic markers on 11 autosomal chromosomes in a series of 49 relapses (23 local recurrences and 26 distant metastases). All of the loss of heterozygosity (LOH) regions reported in primary breast tumors were frequent in both series of relapses. These results suggest that the allelic losses that are common to the different series of samples occur very early during tumor progression. This study points to candidate metastasis-related genes targeted by LOH on chromosome arms 3p21.3, 16q22.2-23.2, and, possibly, 7q31 but provides no clear evidence of LOH affecting previously described metastasis-related genes such as NME1, MTS1, and TSG101.
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PMID:Location of several putative genes possibly involved in human breast cancer progression. 960 47

Distant metastases are the major cause of morbidity and mortality in women with breast cancer. The prediction of this metastatic proclivity is essential in determining prognosis and should allow an appropriate choice of therapy. A critical look at the metastatic process and its phenotypic expression offers an opportunity to identify some of the important events in the process that may relate to prognosis, with the goal of identifying those patients with occult metastases and also sparing systemic treatment in those patients whose tumors have not developed the capacity for distant spread. To evaluate the significance of nm23 and angiogenesis in the metastatic cascade, we used archival material from 163 node-negative breast cancer patients who had a median follow-up of 14 years. All patients underwent mastectomy and received no adjuvant chemotherapy or hormone or radiation therapy. Immunohistochemistry was used to detect nm23-H1 expression, whereas angiogenesis was determined by microvessel count (MVC). We found the 15-year disease-free survival (DFS) to be significantly better in patients with high nm23 compared with low nm23 (91% compared with 70%, P = 0.008). Low MVC is associated with excellent (92%) long-term DFS. In those patients with high MVC, high nm23 allows the identification of a subgroup with significantly higher DFS (90% compared with 66%, P = 0.02). Among high nuclear grade tumors, if nm23 is high, the DFS is significantly better (89% compared with 68%, P = 0.03). Thus, nm23 is still associated with excellent survival, even when there is unfavorable angiogenesis or nuclear grade. Multivariate analysis confirms that nm23 and MVC are important prognostic factors. High MVC appears necessary but not sufficient for metastasis to occur, whereas low nm23 may further contribute to metastatic progression. Both nm23 and MVC contribute valuable information in characterizing the malignant phenotype.
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PMID:The relationship between nm23, angiogenesis, and the metastatic proclivity of node-negative breast cancer. 966 89

The nm23 gene has been proposed as a candidate tumor metastasis suppressor in some human cancers. Sialyl Lewis X (sLex) has been demonstrated to play an important role in the adhesion of human cancer cells to human vascular endothelium, inducing metastasis. Little information has been reported about the correlation between the expression of nm23 and sialylated carbohydrate antigens. In the present study, 102 surgically resected primary breast cancer tissues were sectioned and stained with antibody against nm23-H1 and sLex. Of the 102 cases, 39 (38.2%) cases with a reduced expression of nm23-H1 were observed, and the numbers of sLex-positive cases were 61 (59.8%), respectively. The reduced expression of nm23-H1 and the positive expression of sLex were significantly associated with lymph node involvement. Among the 100 patients who underwent curative surgery, the disease-free survival rate was significantly correlated to both the nm23-H1 and sLex expressions. No interrelated expressions were found between nm23-H1 and sLex. In multivariate analysis using Cox regression model, combination assay of nm23-H1 and sLex expression emerged as independent significant prognostic factors. These results suggest that nm23-H 1 gene and sLex may be involved in different steps of the metastatic process in human breast cancer, and immunohistochemical detection of the combination of sLex and nm23-H1 may be a biologic marker of prognostic significance.
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PMID:Expression of nm23-H1 gene and Sialyl Lewis X antigen in breast cancer. 966 28

The Nm23 gene has been described as an antimetastatic gene; in some studies, disease progression in patients with solid tumours is related to Nm23 protein expression, which can be detected by immunohistochemical procedures. Detection of Nm23-H1 protein in breast cancer may be relevant for the monitoring of patient therapy, provided that the technical procedures are reliable and cost-effective. The aim of the present study was to determine the prognostic significance of Nm23, assessed by quantitative immunocytochemical assays (Nm23 ICAs), under optimal technical conditions. Nm23-H1 ICAs were performed on frozen sections, using an automated immunoperoxidase technique (Ventana) and computer-assisted analysis of digitized colour microscopic images (SAMBA), in a series of 168 breast carcinomas. The results of automated quantitative ICAs were correlated with patients' follow-up (129 months). Nm23-H1 immunocytochemical expression in histological sections of tumours in which more than 3 per cent of the surface area was positively stained was significantly (0.012) correlated with longer metastasis-free survival in both node-positive and node-negative groups of patients (P = 0.032 and P = 0.036, respectively) (Kaplan-Meier log-rank test, NCSS 6.0.1 software). Nm23 expression (cut-point 3 per cent) did not, however, correlate with overall survival, or with the recurrence-free survival. In multivariate analysis (proportional hazards regression, Cox model), the prognostic significance of Nm23 in terms of metastasis-free survival was independent of tumour size and grade, and of histological grade, in the entire cohort of patients. It is concluded that Nm23 immunodetection is only of limited practical clinical relevance in breast carcinoma, even when assessed under optimal technical conditions.
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PMID:Prognostic significance of Nm23/NDPK expression in breast carcinoma, assessed on 10-year follow-up by automated and quantitative immunocytochemical assays. 966 6

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 nm23 gene was originally identified by differential hybridization of metastatic murine melanoma cell lines. Some experimental studies demonstrated a significantly low metastatic potential of melanoma cell lines transfected with the nm23 gene. In this study, we clarified the relationship between intracellular nm23-immunoreactivity and lymph nodal status of human breast cancer. We analyzed 82 surgically removed breast tumors including 67 invasive carcinomas (ductal, lobular and mucinous carcinomas). The nm23 expression was diffusely positive in the benign tumors and non-invasive carcinomas. Of the invasive ductal carcinomas, lymph node metastasis was found in 67.7% (21/31) of the focally positive/negative cases and in 18.2% (4/22) of the diffusely positive cases (p<0.001). Immunohistochemically, advanced margins of invasive carcinomas with lymph node metastasis were shown to be negative for nm23 expression, while intraductal carcinoma components were positive. This observation suggested that focally positive/negative nm23 expression can be a predictor of lymph node metastasis of invasive ductal breast carcinoma.
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PMID:Heterogeneous expression of nm23 gene product as a predictor of lymph nodal status in human breast cancer. 982 22

The active metabolite of vitamin D, 1alpha,25-dihydroxyvitamin D3, can induce differentiation in breast cancer cells; however, it is hypercalcemic in vivo. Therefore, development of non-calcemic analogs of vitamin D has received considerable attention. Recently, we synthesized an analog of vitamin D [1alpha(OH)D5] that exhibits much less calcemic activity than 1alpha,25-dihydroxyvitamin D3. In this study, we evaluated the cell-differentiating action of 1alpha(OH)D5 in breast cancer cells. Following 10 days treatment with 1alpha(OH)D5 [(10-7 M) in UISO-BCA-4], we observed induction of intracytoplasmic casein, intracytoplasmic lipid droplets, ICAM-1, nm23, and specific biomarkers associated with breast cell differentiation. 1alpha(OH)D5 treatment also showed induction of vitamin D receptor and TGFbeta1 proteins. UISO-BCA-4 cells pretreated for 10 days in vitro with 1 microM 1alpha(OH)D5 failed to form tumors when transplanted into athymic mice. Similarly, 4 and 8 ng 1alpha(OH)D5 treatment three times weekly inhibited the growth of UISO-BCA-4 cells injected into athymic mice. These results suggest that this new vitamin D analog may be of significant therapeutic value for breast cancer.
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PMID:Differentiation of human breast carcinoma cells by a novel vitamin D analog: 1alpha-hydroxyvitamin D5. 1060 50

The clinical implications of understanding the invasive and metastatic proclivities of an individual patient's tumour are substantial because the choice of systemic therapy needs to be guided by the likelihood of occult metastasis as well as by knowing when the metastases will become overt. Malignant potential is dynamic, progressing throughout the natural history of a tumour. Required of tumours is the development of critical phenotypic attributes: growth, angiogenesis, invasion and metastagenicity. Characterisation of the extent of tumour progression with regard to these major tumour phenotypes should allow the fashioning of individual therapy for each patient. To examine the clinical parameters and molecularly characterise the metastatic proclivity we have been studying a series of regionally treated breast cancer patients who received no systemic therapy and have long follow-up. Clinically we describe two parameters: metastagenicity - the metastatic proclivity of a tumour, and virulence--the rate at which these metastases appear. Both attributes increase with tumour size and nodal involvement. However, within each clinical group there is a cured population, even in those with extensive nodal involvement, underscoring the heterogeneity of breast cancers within each group and the need for further molecular characterisation. Using biomarkers that characterise the malignant phenotype we have determined that there is progression in the phenotypic changes. Angiogenesis and loss of nm23 are earlier events than the loss of E-cadherin, or abnormalities in TP53. The strongest biomarkers of poor prognosis are p53 and E-cadherin, but even when both are abnormal 42% of node-negative patients are cured indicating that other determinative steps need to occur before successful metastases are established. Identification of these critical later events will further increase the efficacy of determining the malignant capacities of individual tumours.
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PMID:Individual characterisation of the metastatic capacity of human breast carcinoma. 1095 49

Cellular drug resistance and increased metastatic potential are the major obstacles in the successful treatment of cancer with chemotherapy. The aim of this study was to investigate whether the immunohistochemical expression of two proteins implicated in drug resistance (P-glycoprotein and metallothionein) and the product of the suppressor gene nm23 could be related to prognosis in breast cancer. Seventy-two patients with palpable or occult breast carcinoma, not treated with chemotherapy or endocrine therapy, were examined. Immunohistochemical methods were used to determine the expression of P-glycoprotein (PG), metallothionein (MT), nm23, as well as the estrogen receptor (ER), the p53 status, and the Ki67 index. The results were correlated with clinical and morphological features. Cytoplasmic and membrane-specific immunostainings of PG were seen exclusively in tumor cells and identified in 14 of 72 cases (19.4%). Only a statistically significant association with metastases, (p = 0.06) and recurrences (p = 0.1) was observed. MT-positive reaction was identified in the cytoplasm of the tumor cells in 47 (65.3%) cases. Statistical significance was associated with metastases (p = 0.07), but not with death or recurrences. Specific immunostaining of nm23 protein was seen only in the cytoplasm of tumor cells. A positive reaction was observed in 55 of 72 (89.3%) cases. Although a significant association between nm23 protein expression and other morphologic and immunohistochemical variables did not exist, we observed a higher morbidity in patients with the MT-positive/nm23-negative tumor phenotype. Univariate analysis for survival selected the following variables: histologic grade (p = 0.001), ER (p = 0.002), mitotic index (p = 0.005), Ki 67 index (p = 0.068), MT (p = 0.046) and PG (p = 0.085). The Cox model provided the following independent variables: histologic grade (p = 0.021) and metallothionein (p = 0.03). These data confirm the prognosis observed in patients with PG or metallothionein expression as well as the independence of these two variables. It also suggests that nm23 is not necessarily involved in the development of an invasive phenotype.
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PMID:P-glycoprotein, metallothionein and NM23 protein expressions in breast carcinoma. 1098 18


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