Cytoplasmic microtubule-associated motors.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
R A Walker
Publications and source records attributed to R A Walker.
Expression of the pS2 peptide in normal human glandular endometrium during the menstrual cycle: a possible function.
Explore the source record for details and available documents.
Endometrium↗
Immunohistochemical distribution of a breast cancer-associated glycoprotein.
The tissue distribution and specificity of a glycoprotein of M(r) 230,000 kDa which has previously been identified from breast carcinomas in culture and shown to be tumour-associated, has been assessed using a polyclonal antiserum. A wide range of tissues has been examined immunohistochemically. The tissue distribution of the glycoprotein show differences between normal, benign and malignant breast and other epithelial tissues, and are clearly specific for epithelial cells. This glycoprotein as detected by the polyclonal antiserum P5252-2, was either absent or showed a minimal presence in normal breast tissues. Evidence of the expression of the glycoprotein in hyperplastic breast was observed but was considerably less than that seen for carcinomas, for which 70% had greater than 50% of cells exhibiting reactivity with P5252-2. There was no relationship with grade or node status. Similar striking differences in glycoprotein expression between non-neoplastic and neoplastic tissue were observed for stomach, large intestine, thyroid and to lesser extent ovary. The differences in the expression of this glycoprotein between normal and malignant tissues is of obvious clinical and pathological potential.
Biomarkers, Tumor↗
Immunohistochemical expression of tumour-associated glycoprotein and polymorphic epithelial mucin in the human endometrium during the menstrual cycle.
An epitope defined by a second generation murine monoclonal antibody (LU-BCRU-G7) produced against a breast tumour-associated fucosylated glycoprotein of M(r) 230,000 was found to exhibit phase specific reactivity in human endometrium during the menstrual cycle. Distribution and cycle related expression of the LU-BCRU-G7 determinant was different from the staining patterns observed with antibodies that react with the polymorphic epithelial mucins, HMFG 1 and NCRC 11, as determined by immunohistochemistry. Initial expression of the LU-BCRU-G7 determinant was associated with the peri-basal region of glandular epithelial cells with maximal staining during the mid-secretory phase. Diffuse cytoplasmic staining was also observed from day 10 to day 26, with a marked increase in the early secretory phase. Reactivity of NCRC 11 also showed maximal expression in the midsecretory phase with no reactivity detected in early and mid-proliferative phases. The HMFG 1 defined epitope exhibited the opposite pattern of expression with maximal reactivity in the proliferative phase and little or no reactivity in the secretory phase. These findings suggest that expression of the LU-BCRU-G7, HMFG 1 and NCRC 11 defined determinants in the human glandular epithelium of the endometrium is differentially hormonally regulated, and may be of value as markers for endometrial function.
Antigens, Neoplasm↗
Motor vehicle deaths: a rural epidemic.
OBJECTIVE: To determine the magnitude of the discrepancy in injury death rates between urban and rural counties and which types of injury deaths contribute most to this discrepancy. DESIGN: A review of Nebraska death certificates over the period 1985-1989 was undertaken. Counties were divided into four groups according to population. Group I: urban counties (n = 3); group II: counties with a town of greater than 10,000 (n = 9); group III: counties with a total population of greater than 10,000 (n = 19); group IV: counties with a total population of less than 10,000 (n = 62). Age-adjusted death rates for heart disease, cancer, cerebrovascular disease, pneumonia, and injury were tabulated. Injury deaths were further categorized by intentional injury (homicide, suicide), and unintentional injury (motor vehicle-related, falls, drownings, poisoning, farm machinery-related, choking, firearms-related, fire-related and burns). INTERVENTIONS: None. RESULTS: Age-adjusted death rates per 100,000 population (with 95% confidence intervals) in group IV were lower than in group I for heart disease: 209 (193.9-224.1) vs. 227.4 (216.3-238.5); cancer: 135.9 (123.7-148.1) vs. 176.3 (166.6-186.0); cerebrovascular disease: 39.9 (33.3-46.5) vs. 44.6 (39.7-49.5); pneumonia: 19.6 (15.0-24.2) vs. 23.4 (19.8-27.0); and intentional injury deaths: 13.3 (9.5-17.0) vs. 15.1 (12.2-18.0). However, age-adjusted unintentional injury death rates were 54.2% higher in group IV than in group I: 42.7 (35.9-49.5) vs. 27.7 (23.8-31.6). Motor vehicle-related death rates were 93% higher: 23.3 (18.2-28.4) vs. 12.1 (9.5-14.7); and farm machinery-related deaths were 1250% higher: 2.7 (1.0-4.4) vs. 0.2 (-0.1-0.5). CONCLUSION: Age-adjusted unintentional injury death rates are higher in the rural counties of Nebraska, even though death rates for the four other leading causes of death (heart disease, cancer, cerebral vascular disease, and pneumonia) and intentional injury are lower. Although farm machinery-related deaths have the largest percentage difference between rural and urban counties, motor vehicle-related deaths are the major contributor to the unintentional injury death rate discrepancy in rural Nebraska.
Accidents, Traffic↗
The molecular pathology of human breast cancer.
Perhaps one of the most exciting recent developments in breast cancer research is the steadily increasing number of small screen detected lesions which are available for study. These samples will allow a number of questions of key importance to the development and progression of breast cancer to be answered. For example, the relationship between a variety of benign and premalignant lesions and frankly invasive breast carcinomas can be examined to determine the sequence of progression, if indeed such a sequence exists. Subtypes of screen detected lesions may be identified in which different genetic events have occurred, and the relationship between these genetic events and progression may be established. Such studies could identify groups of women for whom no further treatment is required or those for whom adjuvant therapy, radiotherapy or further surgery is indicated. A number of genetic alterations have now been identified that seem to be independent indicators of prognosis. Such alterations include overexpression of c-erbB2 and mutation of TP53. Although there is still some debate about the statistical significance of data from a number of different groups, it seems certain that the status of a number of genes will provide prognostic information to augment existing criteria. There is an urgent need for an examination of a large panel of breast tumours for a number of key genetic alterations and for a critical evaluation of all the changes to existing clinical variables such as clinical stage, grade, survival and relapse times and growth factor receptors. Molecular pathology is providing new and exciting insights into the pathogenesis of human breast cancer, and molecular events associated with inherited breast disease, early stages, progression and metastasis of breast cancer are now becoming better understood.
Breast Neoplasms↗
Alteration of stromal protein and integrin expression in breast--a marker of premalignant change?
Interactions between epithelia and the extracellular matrix are important in the modulation of cellular growth, differentiation, and motility. To investigate the possible roles of these interactions in the neoplastic process, this study examines the expression of the integrin subunits a2, a6, beta 1, and beta 4 and the stromal protein tenascin in 53 breast carcinomas, non-involved breast tissue from 21 of these cases, and 32 normal/benign cases. Frozen tissue and an indirect immunoperoxidase technique were used throughout. Linear staining in relation to the basement membrane was seen for all integrins in the normal/benign cases. The carcinomas showed complete loss of reactivity in 65 per cent of cases for a2, 80 per cent for a6 and beta 4, and 90 per cent for beta 1. Those showing reactivity displayed a diffuse cytoplasmic type of staining. The non-involved breast tissue showed linear basement membrane type staining with a2 and beta 1, but for a6 and beta 4 66 per cent of cases displayed reactivity identical to that of the corresponding tumour. For tenascin, band-like staining around ducts was seen in normal/benign cases, with a diffuse coarse reactivity in all carcinomas. Most non-involved cases stained as for normal breast. The altered a6 beta 4 integrin staining in non-involved tissue in cancerous breast may be an early event in the neoplastic process, and as such, may be of use as a marker of pre-malignant change.
Basement Membrane↗
Differential expression of the mitochondrial gene cytochrome oxidase II in benign and malignant breast tissue.
Comparative analysis of expression levels of genes in benign and malignant tumours of the breast has been performed. Differential screening of cDNA libraries identified four genes of the mitochondrial genome as being expressed at different levels in the two tissues compared, but further investigations showed that only the gene encoding subunit 2 of cytochrome c oxidase (COII) is expressed at significantly higher levels in carcinomas compared with fibroadenomas. The mitochondrial genes encoding subunits 2 and 4 of NADH dehydrogenase, and subunit 6 of F0F1ATPase, were not found to be differentially expressed in carcinomas and fibroadenomas. All four genes were expressed in the epithelium of human breast carcinomas, as shown by in situ hybridization. The expression level of the COII gene is also correlated with carcinoma grade. No gross alterations to the mitochondrial DNA from these tumours could be detected. The possible implications of these results on the behavioural differences between fibroadenomas and carcinomas are discussed.
Adenofibroma↗
Transforming growth factor beta 1 in ductal carcinoma in situ and invasive carcinomas of the breast.
Transforming growth factor beta (TGF-beta) is a multi-functional regulatory protein which can affect growth, immune responses, angiogenesis and the formation of extracellular matrix. Its role in breast carcinomas has been investigated using an antiserum to TGF-beta 1 and immunohistochemistry. 27 ductal carcinomas in situ and 54 invasive carcinomas were examined, employing formalin-fixed, paraffin-embedded material. There was no reactivity in 55.5% of in situ carcinomas in comparison with the invasive tumour where only a third were negative. Prominent reactivity was seen in 11% of in situ tumours, and 20% of invasive carcinomas. There was no correlation between detection of transforming growth factor beta 1, and histological grade, oestrogen receptor status, epidermal growth factor receptor status and Ki-67 labelling for the invasive carcinomas. There was a significant relationship between prominent reactivity and node status, all carcinomas with this degree of staining having metastasised. This, along with the differences between in situ and invasive carcinomas, suggests that TGF-beta 1 may be a determining factor for invasion and metastasis.
Breast Neoplasms↗
Parathyroid hormone related protein and skeletal morbidity in breast cancer.
The presence of parathyroid hormone related protein (PTHRP) in human breast cancers has been assessed by immunohistochemistry using a polyclonal antiserum specific for the mid-region sequence 37-67 in an immunoperoxidase technique. The primary tumours from 155 normocalcaemic, consecutive women with early breast cancer who had been followed up for a minimum of 5 years were assessed. Dewaxed paraffin sections of formalin fixed tissue was used throughout. Positive PTHRP staining was detected in 56% of the cancers and was unrelated to standard prognostic factors, recurrence or survival. However, PTHRP positivity was related to the development of bone metastases (P less than or equal to 0.03) and hypercalcaemic episodes. PTHRP is implicated as the humoral factor responsible for hypercalcaemia associated with breast cancer and tumour positivity may be a useful predictor of which women will develop bone metastases.
Aged↗
Differential expression of translation-associated genes in benign and malignant human breast tumours.
The human gene sequences encoding the translation-associated functions of alpha-subunit of elongation factor 1 (EF-1 alpha) and the ubiquitin carboxyl extension protein (HUBCEP80) have been isolated by differential cDNA screening, and found to have significantly higher levels of expression in fibroadenomas (benign) compared with carcinomas (malignant) of the breast. These data parallel our previous findings that the acidic ribosomal phosphoprotein P2 also has higher expression levels in the benign breast tumours (Sharp et al., 1990). In situ hybridisation has shown these genes to be expressed predominantly in the epithelium of breast tumours.
Adenofibroma↗
Isolation and characterization of a novel gene with differential expression in benign and malignant human breast tumours.
We report the identification of a novel cDNA representing an mRNA showing significantly higher levels of expression in benign breast lesions than in carcinomas. This cDNA was identified by differential screening of a cDNA library generated from a breast carcinoma, and shows consistently higher expression in fibroadenomas than in carcinomas. The expression in both benign and malignant tissues is highest in epithelial cells as determined by in situ hybridization to tissue sections. The nucleotide sequence of the full-length cDNA has been determined, and the deduced protein is highly basic with no signal or transmembrane sequence, but two potential nuclear localization signals. Neither the DNA nor the protein sequence show any significant homology to sequences in current databases. The cDNA hybridizes to multiple sequences within both human and other mammalian genomes, but to single genomic sequences in Drosophila, Physarum and Schizosaccharomyces pombe. This cDNA therefore represents a highly conserved gene sequence. We have identified only one major transcript in human cells, and it seems likely that there are several pseudogenes within the human genome.
Adenofibroma↗
Brain microtubule-associated proteins modulate microtubule dynamic instability in vitro. Real-time observations using video microscopy.
We used video assays to study the dynamic instability behavior of individual microtubules assembled in vitro with purified tau, purified MAP2 or a preparation of unfractionated heat-stable MAPs. Axoneme-nucleated microtubules were assembled from pure tubulin at concentrations between 4 and 9 microM in the presence of MAPs, and observed by video-differential interference contrast microscopy. Microtubules co-assembled with each MAP preparation exhibited the elongation and rapid shortening phases and the abrupt transitions (catastrophe and rescue) characteristic of dynamic instability. Each MAP preparation increased the microtubule elongation rate above that for purified tubulin alone by decreasing the tubulin subunit dissociation rate during elongation. The brain MAPs used in this study reduced the rate of microtubule rapid shortening, but allowed significant loss of polymer during the shortening phase. Purified tau and MAP2 decreased the frequency of catastrophe and increased the frequency of rescue, while the heat-stable MAPs suppressed catastrophe at all but the lowest tubulin concentrations. Thus, each of these MAPs modulates, but does not abolish, dynamic instability behavior of microtubules. We propose a model to explain how MAP2 and tau bind to the microtubule lattice at sites along protofilaments so that the MAPs promote polymerization, but do not significantly block the mechanism of rapid shortening inherent in the tubulin lattice. Rapid shortening, when it occurs, proceeds primarily by the dissociation of short fragments of protofilaments, which contain the bound MAPs.
Animals↗
West Midlands Oncology Association trial of adjuvant chemotherapy in node-negative breast cancer.
Between 1976 and 1984, 574 patients with operable breast cancer and histologically negative axillary lymph nodes were randomly assigned after mastectomy to receive either no further treatment or chemotherapy with oral LMF (fluorouracil, 500 mg, methotrexate, 25 mg, and chlorambucil, 10 mg, on day 1; fluorouracil, 500 mg, and chlorambucil, 10 mg, on day 2). There is no overall survival or relapse-free survival benefit at a median follow-up of 10 years and 8 years, respectively. There are significantly more local relapses in the control group (P less than .01), but an excess of distant relapses in the treated group is not statistically significant (P = .24). A positive treatment effect in small tumors (relapse-free survival, odds ratio = 0.55, P = .01) and a negative effect in progesterone receptor-positive tumors (survival, odds ratios = 2.04, P = .04) is probably ascribable to chance. Analysis of various prognostic factors shows that tumor size and histological grade have a clear effect on both relapse-free interval and survival.
Antineoplastic Combined Chemotherapy Protocols↗
Parathyroid hormone related protein and hypercalcaemia in breast cancer.
OBJECTIVE: To see whether parathyroid hormone related protein has a humoral role in breast cancer. DESIGN: Plasma concentrations and tumour expression of parathyroid hormone related protein were determined (by two site immunoradiometric assay and immunohistochemistry respectively) in women with breast cancer and related to the presence of bone metastases and serum calcium concentrations. SUBJECTS: Plasma concentrations of parathyroid hormone related protein were measured in 57 women with early breast cancer without apparent bone metastases, 28 women with bone metastases, and 13 women with bone metastases and hypercalcaemia. Tissue positivity for parathyroid hormone related protein was determined retrospectively in 106 primary breast tumours from women without apparent bone metastases and 72 tumours from women with bone metastases, 25 of whom subsequently developed hypercalcaemia. RESULTS: Plasma parathyroid hormone related protein concentrations were detectable (greater than 0.23 pmol/l) in 12 (92%) of the 13 hypercalcaemic patients with bone metastases compared with 10 (36%) of the 28 normocalcaemic patients with bone metastases and five (9%) of the 57 normocalcaemic patients without bone metastases. Parathyroid hormone related protein concentrations were significantly higher in hypercalcaemic than normocalcaemic patients with bone metastases. Tumour staining was positive for parathyroid hormone related protein in 22 (88%) of the 25 primary breast cancers from patients with bone metastases. Tumour staining was positive for parathyroid hormone related protein in 22 (88%) of the 25 primary breast cancers from patients with bone metastases who later developed hypercalcaemia compared with 25 (53%) of the 47 from women in this group who remained normocalcaemic and 55 (52%) of the 106 early breast cancers from women without known metastases. CONCLUSION: Tumour derived parathyroid hormone related protein may have an important humoral role in hypercalcaemia associated with metastatic breast cancer.
Bone Neoplasms↗
The expression of c-fos protein in human breast.
The expression of the c-fos protein has been examined in non-malignant and malignant human breast using immunohistochemistry. Since in some cell types expression is associated with differentiation, while in other cells induction is related to growth, the extent of reactivity in carcinomas has been related to tumour grade, oestrogen receptor, epidermal growth factor receptor, and Ki-67 staining. There was a greater degree of staining in the carcinomas than in the normal and benign tissue. In the latter, there was no relationship with menopausal status or with extent of proliferative changes. In all instances, staining was nuclear. Poorly differentiated carcinomas had a greater degree of reactivity, but the converse did not apply to the well differentiated tumours. There was no relationship with oestrogen receptor, epidermal growth factor receptor, or Ki-67 labelling. The greater expression observed in carcinomas correlates with previously reported RNA studies. There is no clear relationship between c-fos protein detection and proliferation or differentiation.
Breast↗
In vitro modulation of cellular localization of milk fat globule membrane antigens in human breast carcinomas.
Alterations in the cellular localization of cell surface components such as the milk fat globule membrane are a common feature of breast carcinomas and relate to the differentiation of a tumour. This study has examined the potential modulation of such components. A group of carcinomas were cultured with and without insulin and/or hydrocortisone and the site of staining for milk fat globule membrane, as detected by the antibodies HMFG 1, HMFG 2, and NCRC 11, was assessed using light microscopic and electron microscopic immunohistochemistry. Modulation of localization, with a shift from cytoplasmic vesicle labelling to submembraneous vesicles/cell surface labelling and intracytoplasmic luminal labelling, was observed in 5 of 14 moderately differentiated and 8 of 11 poorly differentiated carcinomas. Two well differentiated carcinomas continued to show peripheral labelling; three poorly differentiated carcinomas showed no change from cytoplasmic labelling only; and the other carcinomas exhibited heterogeneous localization, making any change difficult to assess. Insulin was required for any change to be observed and it is suggested that this has an effect on the mechanisms for intracellular transport of membrane and secretory proteins.
Antigens, Neoplasm↗
Expression of p53 protein in infiltrating and in-situ breast carcinomas.
Five antibodies directed against the whole or part of p53 protein have been used to detect the protein immunohistochemically in 70 infiltrating breast carcinomas and 10 ductal carcinomas in situ. Mutations are known to occur in different conserved domains, and the antibodies employed spanned the expected sites. p53 protein was identified in 53 per cent of infiltrating carcinomas using the antibodies PAb 240, PAb 1801, C19, and JG8. The antibody PAb 421 detected the protein in 31.5 per cent; all positive with the other antibodies. Well-differentiated oestrogen receptor-positive tumours had a low incidence of p53 detection. Variation in the percentage of reactivity was seen between carcinomas and in some cases between different antibodies in the same cancer. Those carcinomas with a high percentage of positive cells with all antibodies were more likely to have metastasized to nodes, be at an advanced stage, and be oestrogen receptor-negative/epidermal growth factor receptor-positive. There was no significant correlation with c-erbB-2 protein expression or retinoblastoma protein loss. p53 protein was detected in a high proportion of cells in three of the six comedo ductal carcinomas in situ studied but either not at all or at a lower level in tumours of the cribriform type. p53 mutations are common in breast carcinomas, but heterogeneity within individual tumours is frequent. Marked expression of p53 appears to relate to tumour progression.
Antibodies, Monoclonal↗