UMLS:C0006142 - FACTA Search

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Query: UMLS:C0006142 (breast cancer)
160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bax, one of the bcl-2 family genes, is expressed in a number of untransformed cell lines and various breast tissues, whereas only weak or no expression has been detected in breast cancer cell lines and malignant breast tissue. Human breast cancer MCF-7 cells, which have a weak bax gene expression, were stably transfected with pCX2neo bax, encoding human bax; and two unique clones, MCF-7/bax-1 and MCF-7/ bax-2, that expressed different levels of bax were generated. Sensitivity to cisplatin (CDDP) and etoposide (VP-16) was examined and each stable transfectant was more sensitive to these agents than the parental MCF-7 cells. The degree of enhancement in sensitivity to these anticancer agents was dependent on the expression level of bax. The enzyme-linked immunosorbent assay (ELISA), which quantifies DNA damage, demonstrated that this sensitization was due to apoptosis. Thus, we suggest that exogenous bax-alpha overexpression may be one of the factors determining cellular chemosensitivity in MCF-7 breast cancer cells and that it could be applied therapeutically to enhance chemosensitivity in breast cancer cells.
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PMID:Overexpression of bax sensitizes breast cancer MCF-7 cells to cisplatin and etoposide. 930 77

Evaluation of molecular markers by immunohistochemical labelling of tissue sections has traditionally been performed by qualitative assessment by trained pathologists. For those markers with a staining component present outside of the nucleus, there has been no image histometric method available to reliably and consistently define cell interfaces within the tissue. We present a new method of approximating cellular boundaries to define cellular regions within which quantitative measurements of staining intensity may be made. The method is based upon Voronoi tessellation of a defined region of interest (ROI), and requires only the position of the nuclear centroids within the ROI. Here we describe the VORSTAIN software which has been developed based on the Oncometrics CytoSavant Automated Image Cytometry System. To demonstrate this technique, human breast cancer sections immunohistochemically stained for bcl-2 protein and counter-stained with nuclear methyl green stain were evaluated. Intra-observer variation in the measured values was between 1.5-2.6% and inter-observer variation was between 1.8-4.4%. The primary source of variability was due to difficulties in interpreting the exact position of the nuclear centroids. Analysis of mean staining densities for each slide correlated well with subjective scoring performed by two independent pathologists. Using VORSTAIN, significant variation of staining intensities between regions within the same slide was measured for some sections, indicating a large degree of heterogeneity within the tumours. The ability to accurately quantitate the degree of heterogeneity of molecular marker expression within tumours may be a valuable tool in prognostication.
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PMID:A novel image cytometric method for quantitation of immunohistochemical staining of cytoplasmic antigens. 931 24

Bcl-2 protein has been shown to contribute to oncogenesis because it can transform and immortalize cells in cooperation with c-myc, ras, or viral genes. However, in vivo studies have not yet established whether bcl-2 can play a role in metastasis. Here we investigate the potential metastatic role of bcl-2. We introduced the human bcl-2 gene into a low bcl-2 expressing human breast cancer cell line MCF7 ADR. We demonstrate that two bcl-2 overexpressing clones injected intravenously or intramuscularly into nude mice induce a significantly higher number of experimental and spontaneous lung metastases compared to the control transfectant clone. We demonstrate that bcl-2 overexpressing clones are more invasive and migratory in response to chemotactic stimuli than the control transfectant clone. Furthermore, zymographic analysis shows that secretion of 72 and 92 kDa gelatinases increases in the two bcl-2 overexpressing transfectants. Tumors originating from bcl-2 overexpressing clones also show a decrease in the latency period of tumor appearance. In conclusion, our data show that bcl-2 overexpression enhances both tumorigenicity and metastatic potential of MCF7 ADR cells by inducing metastasis-associated properties.
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PMID:Bcl-2 overexpression enhances the metastatic potential of a human breast cancer line. 933 47

To evaluate the prognostic significance of bcl-2, we investigated the correlation of bcl-2 expression with the established indicators of prognosis and tumor behavior in breast cancer. This study included a patient group of 91 histologically diagnosed female breast carcinomas. To determine the bcl-2 immunoreactivity, we used a monoclonal antibody directed against the bcl-2 protein by immunohistochemistry from paraffin-embedded tissue in a series of 91 women with breast cancer. Interpretable DNA histograms were obtained from 84 patients. The median age at diagnosis was 45.5 years and the median follow-up time was 30.5 months. Forty-eight (52.7%) cancers showed the bcl-2 immunoreactivity in the cytoplasm. The nonneoplastic portion of ductal epithelial cells and normal lymphocytes were usually stained with bcl-2 antibody. Estrogen receptors (ER)(p < 0.001) and progesterone receptors (PR)(p < 0.001) showed strong positive correlation with bcl-2 immunoreactivity. The histologic grade (p < 0.05) and nuclear grade (p < 0.01) also showed positive relationships with bcl-2 positivity but tumor size (p > 0.05) and DNA ploidy (p > 0.05) were not related with it. The bcl-2 positive patients showed longer survival (p < 0.05) compared to bcl-2 negative tumors in univariate analysis (Kaplan-Meier life table analysis). Using multivariate analysis with Cox regression, bcl-2 (p > 0.05), nuclear grade (p > 0.05), ER status (p > 0.1) and PR status(p > 0.1) were not reliable indicators for overall survival except histologic grade (p < 0.05). Our results suggest that bcl-2 expression may be related to hormonal regulation and tumor differentiation in breast carcinoma. Larger patient study groups with a longer follow-up period will be helpful to clarify the prognostic significance of bcl-2.
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PMID:Correlations of bcl-2 expression with clinicopathological features in breast cancer. 933 28

Extensive research has led to accumulation of common hereditary evidence concerning ovarian and breast cancer, suggesting that these two cancers can be considered as one type. Subsequently, women with breast cancer are susceptible to the risk of developing ovarian cancer. Highly expressed oncogenes such as bcl-2, HER2/neu and others or mutated suppressor genes such as p53 or BRCA1 have been characterised as hereditary susceptibility genes leading to syndromes such as breast/ovarian cancer syndrome, Li-Fraumeni and others. Furthermore, these genetic alterations can cause potent chemoresistance by inhibiting induction of apoptosis after DNA damage caused by chemotherapy and/or radiotherapy. Presently, molecular onco-biology has enabled us not only to detect susceptibility to ovarian and breast cancer but also ways to inhibit their further progression or even circumventing chemoresistance mechanisms after their development by gene therapy using delivery vectors such as liposomes or viruses, by which we can replace wild-type tumour suppressor genes or by using antigene, antisense oligonucleotides and antisense RNA leading to reduced oncogene expression, enabling induction of apoptosis after DNA damage into chemoresistant tumour cells. Furthermore efflux-genes such as MDR-1 or MRP can be circumvented, suicide-genes can be employed which can facilitate sensitivity by encoding enzymes capable of converting inactive forms of a drug into toxic antimetabolites and immunotherapy can be achieved, by transfection of tumour cells with adenoviral vectors encoding immunomodulators such as IL-2 or MHC molecules. Thus, molecular biology appears to be a very strong element for the screening, diagnosis, therapy and prognosis of ovarian and breast cancer. However, consistent future research is greatly needed because many points concerning ovarian and breast cancer genetics are still unknown. Finally, we strongly believe that gene therapy could be extremely useful when is combined with conventional therapy against ovarian and breast tumours.
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PMID:Molecular aspects of breast and ovarian cancer. 937 59

Some women with benign breast disease eventually develop breast cancer. The mammary gland undergoes tissue remodelling according to hormonal influences, involving a balance between quiescence, proliferation, and mechanisms of cell death. Proliferation and/or apoptotic events could therefore be investigated to help understand the mechanisms of benign lesion formation and identify mastopathies with a poor prognosis. bcl-2 expression was analysed by immunohistochemistry in 75 benign mastopathies. Protein levels were quantitated with an image analyser in various epithelial structures on frozen sections, including adenoses, fibroadenomas, ductal epithelial hyperplasias, cysts, and apparently normal surrounding lobules and ducts. bcl-2 levels were equivalent in apparently normal lobules and ducts, as well as in cysts and ductal hyperplasias. bcl-2 staining was significantly higher in fibroadenomas, known to be of lobular origin [mean = 10.1, quantitative immunochemistry score (QIC) arbitrary units (AU), n = 19], than in normal lobules (mean = 5.1 AU, n = 43, P = 7 x 10(-5). bcl-2 levels in normal lobules and ducts varied according to the menstrual cycle, being higher during the follicular than the luteal phase (P = 1.8 x 10(-2) and P = 1.7 x 10(-2), respectively). This was further supported by a statistical link (P = 5 x 10(-3) between high levels of circulating progesterone and weak bcl-2 staining in lobules and ducts. This progesterone-dependent variation was absent in fibroadenomas. No statistical correlation was found between bcl-2 expression and circulating levels of oestradiol, and follicle-stimulating or luteotrophic hormones. Although these are only preliminary results, they suggest an influence of progesterone on bcl-2 expression which might be lost in fibroadenomas. A hypothesis is proposed concerning the potential involvement of altered regulation of the apoptotic process in the formation of such benign lesions.
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PMID:Variation of bcl-2 expression in breast ducts and lobules in relation to plasma progesterone levels: overexpression and absence of variation in fibroadenomas. 939 34

Understanding the fundamental mechanism of apoptosis is crucial to developing therapeutic strategies for controlling apoptosis in diseased tissues. We are using model systems with relevance to cancer treatment to investigate the mechanism of apoptosis. Subtraction hybridization cloning was used to identify transcripts present at higher levels in regressing vs. normal prostate; these may be important for apoptosis. One of the genes cloned from regressing prostate is also upregulated in the murine W7.2 lymphocyte cell line induced to undergo apoptosis by treatment with the synthetic glucocorticoid, dexamethasone. This gene encodes a mu class glutathione S-transferase (EC 2.5.1.18), a protein that can protect the cell against oxidative stress by repairing oxidized lipids, proteins, and DNA. Glutathione S-transferase expression does not increase with dexamethasone treatment of lymphocyte cell lines expressing nonfunctional glucocorticoid receptors or a mutation in the apoptotic pathway. Other antioxidant defenses, including catalase (EC 1.11.1.6) and superoxide dismutase (EC 1.15.1.1), decline following dexamethasone treatment of W7.2 cells. Overexpression of the bcl-2 oncogene protects these cells against dexamethasone-mediated apoptosis and prevents the decrease in antioxidant enzyme activity. These findings support the hypothesis that control of the cellular redox state is important to the mechanism of glucocorticoid-mediated lymphocyte apoptosis. Another model system we are using is tumor necrosis factor-alpha treatment of MCF-7 human breast cancer cells. Our preliminary results suggest that, in this system, activation of nuclear factor-kappa B and increased expression of manganese superoxide dismutase may afford protection from apoptosis.
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PMID:Modulation of antioxidant defenses during apoptosis. 940 33

Patients with primary breast carcinoma with one to three axillary lymph node metastases but without distant metastases (n1-3) in Japan have been shown to have a 10-year disease-free survival rate of > 60%. It would be reasonable to divide n1-3 Japanese breast cancer patients into groups with high- or low-risk for recurrence and to consider post-operative adjuvant therapy. In the present study, we analyzed 228 consecutive Japanese patients with n1-3 breast cancer who underwent radical mastectomy and were followed up for a median time of 11.0 years. The expression of bcl-2, p53 and c-erbB-2 proteins in the primary tumors was examined immunohistochemically and their prognostic roles were also analyzed along with conventional clinicopathologic indicators. bcl-2 expression was correlated with positive estrogen receptor status and inversely correlated with p53, c-erbB-2 and histologic grade. Univariate analysis showed that bcl-2, p53 and c-erbB-2 expression were prognostic indicators of the patient's group as well as node status, histologic grade, tumor size, age at diagnosis, menopausal status and estrogen receptor status. Cox's regression analysis demonstrated that the number of nodes involved, menopausal status, p53 and bcl-2 were independent predictors for overall survival and that histologic grade and the number of nodes involved were independent predictors for disease-free survival. These results suggest that bcl-2 expression in combination with p53 and c-erbB-2 expression, the number of lymph node metastases, histologic grade and menopausal status are useful in selecting subgroups of n1-3 breast cancer patients with good or poor prognoses.
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PMID:Prognostic indicators for breast cancer patients with one to three regional lymph node metastases, with special reference to alterations in expression levels of bcl-2, p53 and c-erbB-2 proteins. 943 97

Two in vitro models are compared to investigate whether cellular configuration or composition of the matrix in which the cells are cultured influences growth and/or prognostic parameters. T47D, MCF-7 and Hs578T breast cancer cell lines were cultured on two different matrices (agarose and collagen). Growth curves, biological markers (Ki-67, p53 and bcl-2) and the expression of hemostatic parameters were studied. The tested hemostatic parameters were urokinase-type plasminogen activator, tissue-type plasminogen activator and plasminogen activator inhibitor as fibrinolytic parameters and von Willbrand factor, tissue factor, antithrombin III, factor X and factor Xa as coagulation parameters. We found that T47D and MCF-7 formed spheroids in both matrices. Hs578T did not form spheroids; instead, the cells remained single cells in the agarose matrix and grew invasively through the collagen matrix. Expression of the biological markers was similar for spheroids and monolayers. In contrast, a clear difference in expression of hemostatic factors by spheroids and monolayers was found.
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PMID:Cellular arrangement of human breast cancer cell lines determines hemostatic parameters. 948 61

Core needle biopsies (CNB) are often used for the diagnosis of breast lesions. In some breast cancer patients, e.g., those treated with preoperative chemotherapy, the CNB specimen might be the only pretreatment tissue sample available for studies of prognostic and predictive markers. Our purpose was to evaluate whether marker studies performed on CNB specimens accurately reflect the marker status of the tumor. Immunostaining for five commonly used prognostic and predictive markers was performed on both CNB and subsequent excision specimens from 56 consecutive patients who had a CNB with carcinoma followed by excision of the tumor. None of the patients received radiotherapy or chemotherapy between the CNB and the excision. Paraffin sections of the CNB and excision specimens were immunostained for bcl-2, estrogen receptor (ER), c-erbB-2, and p53. These markers were scored as positive or negative. Microvessel density (MVD) was scored as a continuous variable on sections immunostained for Factor VIII-related antigen by calculating the average number of microvessels in three 224x fields of highest tumor vascularity ("hot spots"). Immunostaining results for bcl-2, ER, c-erbB-2, and p53 on the CNB and the corresponding excision specimens were 100% concordant. Although there was significant correlation between MVD on the CNB specimens and the corresponding excisions (r = 0.507, P = 0.0002), the mean MVD on the CNB and corresponding excision specimens differed by more than 10% in 85.7% of cases, with differences ranging from 4.3 to 233.3%. MVD was higher in the CNB than in the excision specimens in 30 (61.2%) of 49 cases. In conclusion, in all of the cases studied, accurate results for the dichotomously scored markers bcl-2, ER, c-erbB-2, and p53 were obtained on CNB specimens. In contrast, in most cases, MVD, which was scored as a continuous variable, could not be reliably assessed on the CNB specimen.
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PMID:Do prognostic marker studies on core needle biopsy specimens of breast carcinoma accurately reflect the marker status of the tumor? 952 72

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