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Biomedical subjects

E R Fearon

Publications and source records attributed to E R Fearon.

At least 37 records · Page 2Linked to original sources
PubMed1998

Expression of c-met is a strong independent prognostic factor in breast carcinoma.

BACKGROUND: The c-met protooncogene encodes the met protein, the receptor for scatter factor/hepatocyte growth factor, a growth factor that modulates the motility and stable interaction of the epithelial cells. This study assesses the expression of met receptor in breast carcinoma and its prognostic value with respect to survival. METHODS: Immunofluorescence was used to evaluate 91 archival breast carcinoma specimens using a polyclonal antibody to the cytoplasmic domain of the receptor. Cases were scored by two pathologists on a percentage basis and then converted to binary scores (positive or negative) on the basis of a bimodal distribution. RESULTS: Strong expression of met was found in 20 invasive ductal breast tumor specimens (22%). The 5-year survival of patients whose tumors showed decreased met expression was 89%, in contrast to a 52% 5-year survival rate in patients whose tumors expressed met (P = 0.008). This trend also was observed in patients without lymph node metastases at presentation, in whom met negative patients had a 95% 5-year survival compared with only 62% for met positive patients (P = 0.006) Multivariate analysis using the Cox proportional hazards model showed met expression to be an independent predictor of survival, with a predictive value nearly equivalent to that associated with lymph node status. CONCLUSIONS: The authors conclude that expression of met in patients with invasive ductal carcinoma of the breast is a strong, independent predictor of decreased survival and may be a useful prognostic marker with which to identify a subset of patients with more aggressive disease.

Adult↗
PubMed1998

Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation.

The tumour suppressor gene PTEN , which maps to 10q23.3 and encodes a 403 amino acid dual specificity phosphatase (protein tyrosine phosphatase; PTPase), was shown recently to play a broad role in human malignancy. Somatic PTEN deletions and mutations were observed in sporadic breast, brain, prostate and kidney cancer cell lines and in several primary tumours such as endometrial carcinomas, malignant melanoma and thyroid tumours. In addition, PTEN was identified as the susceptibility gene for two hamartoma syndromes: Cowden disease (CD; MIM 158350) and Bannayan-Zonana (BZS) or Ruvalcaba-Riley-Smith syndrome (MIM 153480). Constitutive DNA from 37 CD families and seven BZS families was screened for germline PTEN mutations. PTEN mutations were identified in 30 of 37 (81%) CD families, including missense and nonsense point mutations, deletions, insertions, a deletion/insertion and splice site mutations. These mutations were scattered over the entire length of PTEN , with the exception of the first, fourth and last exons. A 'hot spot' for PTEN mutation in CD was identified in exon 5 that contains the PTPase core motif, with 13 of 30 (43%) CD mutations identified in this exon. Seven of 30 (23%) were within the core motif, the majority (five of seven) of which were missense mutations, possibly pointing to the functional significance of this region. Germline PTEN mutations were identified in four of seven (57%) BZS families studied. Interestingly, none of these mutations was observed in the PTPase core motif. It is also worthy of note that a single nonsense point mutation, R233X, was observed in the germline DNA from two unrelated CD families and one BZS family. Genotype-phenotype studies were not performed on this small group of BZS families. However, genotype-phenotype analysis inthe group of CD families revealed two possible associations worthy of follow-up in independent analyses. The first was an association noted in the group of CD families with breast disease. A correlation was observed between the presence/absence of a PTEN mutation and the type of breast involvement (unaffected versus benign versus malignant). Specifically and more directly, an association was also observed between the presence of a PTEN mutation and malignant breast disease. Secondly, there appeared to be an interdependent association between mutations upstream and within the PTPase core motif, the core motif containing the majority of missense mutations, and the involvement of all major organ systems (central nervous system, thyroid, breast, skin and gastrointestinal tract). However, these observations would need to be confirmed by studying a larger number of CD families.

Chromosome Mapping↗
PubMed1998

The expression of p120ctn protein in breast cancer is independent of alpha- and beta-catenin and E-cadherin.

Several studies have reported loss or alteration of expression of E-cadherin in breast cancer and more recently changes in levels of expression of the catenins. We used immunofluorescence to examine E-cadherin, alpha-catenin, beta-catenin, and p120ctn (formerly p120CAS) expression in 91 cases of invasive ductal carcinoma. As expected, all four proteins co-localize to the junctional regions of the cells. Although nuclear localization has been described for beta-catenin in colonic polyps, no examples were found in these breast cancer cases. We found that, although alteration is common in the catenins and E-cadherin, complete loss, as exemplified by E-cadherin in lobular carcinoma (where E-cadherin is frequently mutated), is rarely seen. In contrast, the catenin-related protein p120ctn shows an expression pattern that is significantly unrelated to the other catenins (or E-cadherin), including complete loss of expression in approximately 10% of the cases. No statistically significant correlations with traditional prognostic indicators were observed with any of these proteins. We conclude 1) that expression of E-cadherin and alpha- and beta-catenin are generally retained at the membrane although frequently reduced or altered, 2) that complete loss of p120ctn expression is seen in approximately 10% of the cases, and 3) that there is a significant correlation in the expression of E-cadherin and the catenins but no correlation between these molecules and p120ctn, suggesting an absence of coordinate regulation.

Adult↗
PubMed1997

Characterization of human homologs of the Drosophila seven in absentia (sina) gene.

Studies of Drosophila photoreceptor development have illustrated the means by which signal transduction events regulate cell fate decisions in a multicellular organization. Development of the R7 photoreceptor is best understood, and its formation is dependent on the seven in absentia (sina) gene. We have characterized two highly conserved human homologs of sina, termed SIAH1 and SIAH2. SIAH1 maps to chromosome 16q12 and encodes a 282-amino-acid protein with 76% amino acid identity to the Drosophila SINA protein. SIAH2 maps to chromosome 3q25 and encodes a 324-amino-acid protein that shares 68% identity with Drosophila SINA and 77% identity with human SIAH1. SIAH1 and SIAH2 were expressed in many normal and neoplastic tissues, and only subtle differences in their expression were noted. However, one of three murine homologs, Siah1B, was strongly induced in fibroblasts undergoing apoptotic cell death. While a previous study suggested that SINA was a nuclear protein, epitope-tagged SINA and SIAH1 proteins were found in the cytoplasm of Drosophila and mammalian cells. Their substantial evolutionary conservation, role in specifying cell fate, and activation in apoptotic cells suggest the SIAH proteins have important roles in vertebrate development. Furthermore, given the role of sina in Drosophila photoreceptor development, SIAH2 is a candidate for the Usher syndrome type 3 gene at chromosome 3q21-q25.

Adult↗
PubMed1997

Human cancer syndromes: clues to the origin and nature of cancer.

More than 20 different hereditary cancer syndromes have now been defined and attributed to specific germline mutations in various inherited cancer genes. Collectively, the syndromes affect about 1 percent of cancer patients. An individual who carries a mutant allele of an inherited cancer gene has a variable risk of cancer that is influenced by the particular mutation, other cellular genes, and dietary, lifestyle, and environmental factors. Though hereditary cancer syndromes are rare, their study has provided powerful insights into more common forms of cancer. Somatic mutations in sporadic cancers frequently alter the inherited cancer genes, and the functions of cell signaling pathways have been illuminated by study of the affected genes. Further investigation of inherited mutations that affect susceptibility to cancer will aid efforts to effectively prevent, detect, and treat the disease.

Alleles↗
PubMed1997

Mammalian homologs of seven in absentia regulate DCC via the ubiquitin-proteasome pathway.

DCC (deleted in colorectal cancer) is postulated to function as transmembrane receptor for the axon and cell guidance factor netrin-1. We report here that the DCC cytoplasmic domain binds to proteins encoded by mammalian homologs of the Drosophila seven in absentia (sina) gene, as well as Drosophila Sina. Sina has a critical role in R7 photoreceptor development and shows upward of 85% amino acid identity with its mammalian homologs (termed Siahs), but the function of the Sina/Siah proteins has not been defined. We sought, therefore, to characterize further their interaction with DCC. Immunofluorescence studies suggested the Sina/Siah proteins localized predominantly in the cytoplasm and in association with DCC. DCC was found to be ubiquitinated and the Sina/Siah proteins regulated its expression. Proteasome inhibitors blocked the effects of Sina/Siah on DCC, and the Sina/Siah proteins interacted with ubiquitin-conjugating enzymes (Ubcs). A mutant Siah protein lacking the amino-terminal Ubc-binding sequences complexed with DCC, but did not degrade it. The in vivo interaction between Sina/Siah and DCC was confirmed through studies of transgenic Drosophila lines in which DCC and Sina were ectopically expressed in the eye. Taken together, the data imply that the Sina/Siah proteins regulate DCC and perhaps other proteins via the ubiquitin-proteasome pathway.

Animals↗
PubMed1997

Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts.

NIH 3T3 fibroblasts stably transformed with a constitutively active isoform of p21(Ras), H-RasV12 (v-H-Ras or EJ-Ras), produced large amounts of the reactive oxygen species superoxide (.O2-). .O2- production was suppressed by the expression of dominant negative isoforms of Ras or Rac1, as well as by treatment with a farnesyltransferase inhibitor or with diphenylene iodonium, a flavoprotein inhibitor. The mitogenic activity of cells expressing H-RasV12 was inhibited by treatment with the chemical antioxidant N-acetyl-L-cysteine. Mitogen-activated protein kinase (MAPK) activity was decreased and c-Jun N-terminal kinase (JNK) was not activated in H-RasV12-transformed cells. Thus, H-RasV12-induced transformation can lead to the production of .O2- through one or more pathways involving a flavoprotein and Rac1. The implication of a reactive oxygen species, probably .O2-, as a mediator of Ras-induced cell cycle progression independent of MAPK and JNK suggests a possible mechanism for the effects of antioxidants against Ras-induced cellular transformation.

3T3 Cells↗
PubMed1997

Identification and characterization of neogenin, a DCC-related gene.

DCC (deleted in colorectal cancer), a candidate tumor suppressor gene located in chromosome band 18q21.2, encodes a transmembrane protein of 1447 amino acids. Neogenin, a protein with nearly 50% amino acid identity to DCC, was recently identified because of its dynamic expression in the developing nervous system and gastrointestinal tract of the chicken. To explore a role for the human neogenin (NGN) gene in cancer, we have isolated cDNAs for two alternatively spliced forms of NGN, encoding proteins of 1461 and 1408 amino acids. Fluorescence in situ hybridization studies (FISH) localized NGN in chromosome band 15q22, a region infrequently affected by alterations in cancer. NGN transcripts of about 7.5 and 5.5 kb were detected in all adult tissues studied. In contrast to the frequent loss of DCC expression, no alterations in NGN expression were observed in more than 50 cancers studied, including glioblastoma, medulloblastoma, neuroblastoma, colorectal, breast, cervical and pancreatic cancer cell lines and xenografts. Based on their sequence conservation and similar expression during development, DCC and NGN may have related functions. However, the chromosomal location and ubiquitous expression of NGN in various human tumors suggest it is infrequently altered in cancer.

Adult↗
PubMed1997

Loss of DCC expression and glioma progression.

The deleted in colorectal cancer (DCC) gene, a candidate tumor suppressor gene on chromosome 18q21, encodes a neural cell adhesion molecule family protein that is most highly expressed in the nervous system. To address the hypothesis that DCC may play a role in glioma development and/or progression, we examined DCC expression by immunohistochemistry in 57 resected human astrocytic tumors. Overall, low-grade astrocytomas were predominantly DCC positive (15 of 16, or 94%), whereas high-grade tumors significantly less often expressed the DCC protein (27 of 41, or 66%; P = 0.03). We were able to directly assess the relationship between DCC expression and tumor progression in 15 patients who initially presented with a low-grade astrocytoma and subsequently recurred with a glioblastoma. Within this panel of paired lesions from the same patient, 14 of 15 (93%) low-grade tumors expressed the DCC protein, whereas only 7 of 15 (47%) corresponding glioblastomas were DCC positive. We also observed that secondary glioblastomas resulting from malignant progression of low-grade astrocytomas were more often DCC negative (8 of 15, or 53%) compared with primary or de novo glioblastomas (6 of 26, or 23%; P = 0.05). These findings implicate DCC inactivation in glioma progression and also demonstrate that DCC expression is preferentially, but not exclusively, lost in the genetic pathway to secondary glioblastoma multiforme.

Animals↗
PubMed1997

Transcriptional defects underlie loss of E-cadherin expression in breast cancer.

Decreased expression of E-cadherin (E-cad), a calcium-dependent cell adhesion molecule, has been seen in many different epithelial cancers. Although somatic mutations in the E-cad gene have been identified in a small subset of tumors, in the majority of cancers, the mechanisms underlying loss of E-cad expression are poorly understood. We have cloned the human E-cad promoter and defined its critical components in functional assays. In eight human breast cancer cell lines, there was a striking correlation between endogenous E-cad gene expression and E-cad promoter activity observed following the introduction of reporter gene constructs into the lines. These and other observations suggest that defects in trans-acting pathways regulation E-cad expression are the primary basis for the loss of its expression in most breast cancers. The results have significant implications for understanding the gene expression differences that underlie tumor heterogeneity and progression events in breast and other epithelial cancers.

Antimetabolites, Antineoplastic↗
PubMed1996

The DCC protein and prognosis in colorectal cancer.

BACKGROUND: Allelic loss of chromosome 18q predicts a poor outcome in patients with stage II colorectal cancer. Although the specific gene inactivated by this allelic loss has not been elucidated, the DCC (deleted in colorectal cancer) gene is a candidate. We investigated whether the expression of the DCC protein in tumor cells is a prognostic marker in colorectal carcinoma. METHODS: The expression of DCC was evaluated immunohistochemically in 132 paraffin-embedded samples from patients with curatively resected stage II and III colorectal carcinomas. The Cox proportional-hazards model was used to adjust for covariates including age, sex, tumor site, degree of tumor differentiation, and use of adjuvant therapy. RESULTS: The expression of DCC was a strong positive predictive factor for survival in both stage II and stage III colorectal carcinomas. In patients with stage II disease whose tumors expressed DCC, the five-year survival rate was 94.3 percent, whereas in patients with DCC-negative tumors, the survival rate was 61.6 percent (P<0.001). In patients with stage III disease, the respective survival rates were 59.3 percent and 33.2 percent (P=0.03). CONCLUSIONS: DCC is a prognostic marker in patients with stage II or stage III colorectal cancer. In stage II colorectal carcinomas, the absence of DCC identifies a subgroup of patients with lesions that behave like stage III cancers. These findings may thus have therapeutic implications in this group of patients.

Aged↗
PubMed1996

DCC: is there a connection between tumorigenesis and cell guidance molecules?

Based on the findings reviewed above, DCC remains a strong candidate for the tumor suppressor gene in the 18q21 region that is presumed to be frequently inactivated in colorectal and a number of other cancer types. Although little is known of the specific mechanisms that account for the loss of its expression in most cancers, the recent studies demonstrating an association between loss of DCC expression in colorectal cancers and poor prognosis imply that DCC inactivation may have very significant effects on the cancer cell phenotype. DCC function in normal and cancer cells is still relatively poorly understood. However, recent studies have begun to provide some insights. Based on the results of a number of recent studies, DCC appears likely to have a role in significant role in differentiation, cell fate determination, and migration in the nervous system and perhaps other tissues as well. Though many additional studies are needed to characterize DCC function more definitively, it seems reasonable to predict that such studies are likely to provide new insights into growth control pathways in normal and cancer tissues.

Cell Differentiation↗
PubMed1996

EJ-Ras inhibits phospholipase C gamma 1 but not actin polymerization induced by platelet-derived growth factor-BB via phosphatidylinositol 3-kinase.

Transformation of fibroblast-like cells (NIH 3T3) by a constitutively activated GTP-bound isoform of p21ras (EJ-Ras) produces morphogenic changes characterized by decreased attachment to the substratum, with retraction and rounding of the cell body. Transformed fibroblasts lose their "stressed" conformation and adopt a "relaxed" morphology. The specific molecular mechanisms responsible for these changes remain uncharacterized. We found that EJ-Ras transformation of NIH 3T3 cells decreased the cellular content of polymerized actin, particularly at the expense of actin stress fibers, but induced the accumulation of actin filaments in peripheral ruffling membranes. Polymerization of actin could be induced in EJ-Ras-transformed cells by exposure to platelet-derived growth factor (PDGF)-BB to an extent similar to that observed in wild-type NIH 3T3 cells. In EJ-Ras cells, actin polymerization was independent of phospholipase C gamma 1 (PLC gamma 1) activity, because inositol tris-phosphate (IP3) production observed in control NIH 3T3 cells in response to PDGF-BB was absent. Although PDGF-BB did stimulate tyrosine phosphorylation of PLC gamma 1, the phospholipase was strongly inhibited by an inhibitory factor present in the cytoplasm of EJ-Ras-transformed cells. In addition, cytoplasmic extracts of EJ-Ras, but not of control cells, inhibited phosphatidylinositol 4,5-diphosphate (PIP2) hydrolysis catalyzed by a recombinant PLC gamma 1 in vitro. Although PIP2 hydrolysis could not contribute to the reorganization of the actin cytoskeleton induced by PDGF-BB in EJ-Ras-transformed cells, phosphatidylinositol 3-kinase (PI3-K) was necessary for actin polymerization. Wortmannin, a specific PI3-K inhibitor, not only blocked actin polymerization in both control and EJ-Ras-transformed cells but actually led to rapid actin depolymerization when these cells were exposed to PDGF-BB. Thus, in EJ-Ras-transformed cells, cell morphogenic changes in response to PDGF-BB rely importantly on PI3-K and can occur in the complete absence of IP3 production despite tyrosine phosphorylation of PLC gamma 1.

3T3 Cells↗
PubMed1996

Loss of DCC expression in neuroblastoma is associated with disease dissemination.

DCC, a candidate tumor suppressor gene from chromosome 18q21, is most highly expressed in the developing nervous system. In vitro studies suggest a role for DCC in neuronal differentiation, and 18q allelic loss occurs in a subset of neuroblastomas. To address the hypothesis that loss of DCC function may contribute to tumorigenesis in cells of neural origin, we utilized a combination of RNase protection, immunoblotting, and immunohistochemical approaches to characterize DCC expression in 62 primary neuroblastomas and 16 neuroblastoma cell lines. The DCC protein was undetectable in 38% of the primary tumors and 56% of the cell lines. Of note, primary tumors lacking DCC expression were more likely to have been obtained from patients with disseminated or stage D disease (P = 0.01). In addition, loss of DCC expression was observed in three of six primary tumors from stage DS patients. No consistent relationship between the loss of DCC expression and N-myc amplification was observed in our studies. Our findings suggest that loss of DCC expression may contribute to the dissemination of neuroblastoma cells, perhaps through alterations in growth and differentiation pathways distinct from those regulated by N-myc.

Cell Adhesion Molecules↗
PubMed1995

DCC expression is altered by multiple mechanisms in brain tumours.

The DCC (deleted in colorectal cancer) candidate tumor suppressor gene spans greater than 1350 kilobases at chromosomes 18q21.1 and encodes a transmembrane protein of unknown function. Although DCC is expressed in a number of adult tissues, its expression is highest in the brain and we have, therefore, undertaken studies to determine if DCC inactivation might contribute to tumors arising there. Decreased or absent DCC protein expression was noted in more than 50% of the thirty brain tumors studied. Although specific mutations in the DCC gene were not identified, a variety of mechanisms appeared to contribute to the altered DCC expression, including allelic loss, aberrant splicing of transcripts and allele-specific loss of transcripts. In total, the data suggest that DCC inactivation may be important in brain tumor pathogenesis.

Amino Acid Sequence↗