Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0007097 (carcinoma)
152,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A new approach for the treatment of breast cancer could be the use of progesterone antagonists. These compounds were originally developed for the inhibition of progesterone-dependent processes and have been shown to be effective in inhibition of nidation and interruption of pregnancy. Although the roles of progesterone and the progesterone receptor in control of cell growth remain unclear, it was found in progesterone receptor positive mammary carcinoma cell lines that the antiprogestin, Mifepristone, had an inhibitory effect on cell growth and a growth-inhibiting action on the DMBA-induced mammary carcinoma of the rat. We have shown that the progesterone antagonists, Onapristone and ZK 112993, which possess a reduced antiglucocorticoid activity compared to Mifepristone, exert a strong tumor-inhibiting effect in a panel of hormone-dependent mammary tumor models. The effects of these compounds were in some systems superior to those of tamoxifen or high dose progestins and comparable to ovariectomy. Although prerequisites for their antiproliferative potency are an affinity to the progesterone receptor as well as a sufficient number of available receptors in the tumors, the strong tumor inhibiting potential of the antiprogestins cannot be explained by a classical anti-hormonal mechanism. Surprisingly, the antitumor activity is evident in spite of elevated serum levels of ovarian and pituitary hormones. It was established by morphometric procedures that treatment with Onapristone triggers differentiation of the mitotically active polygonal tumor epithelial cell towards secretory active glandular structures and acini. All our quantitative light and electron microscopic data indicate that the antitumor action of antiprogestins is accompanied by the initiation of terminal differentiation leading to (apoptotic) cell death. Finally, our flow cytometry studies revealed an accumulation of the tumor cells in the G0G1 phase of the cell cycle, which may result from induction of differentiation since a differentiation-specific G1 arrest has already been proposed for other stem cell systems. It can be concluded from these data that the progesterone receptor antagonists differ in their mode of action from compounds used in established endocrine treatment strategies for mammary carcinoma. The ability of progesterone antagonists like Onapristone to reduce the number of cells in S-phase may offer a significant clinical advantage, since it is established that the S-phase fraction is a highly significant predictor of disease-free survival among axillary node-negative patients with diploid mammary tumors.
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PMID:Progesterone antagonists: tumor-inhibiting potential and mechanism of action. 156 10

Compared to other techniques, the ability to detect estrogen and progesterone receptors by immunocytochemical analysis in formalin-fixed, paraffin-embedded sections has clear advantages, including the ability to assay small biopsy specimens, fine-needle aspirate samples, and archival material. Twenty-two cases of breast carcinoma were evaluated for estrogen and progesterone receptors by immunocytochemical analysis and enzyme immunoassay. Using a true color-based image analysis system, histograms of area versus the optical density of the positive staining nuclei were generated. A binary decision algorithm was derived from these histogram parameters by the CART computer program. Estimates generated by the algorithm for image analysis/immunocytochemical analysis had a 90% concordance with the enzyme immunoassay values. It is concluded that quantitative immunocytochemical results for estrogen and progesterone receptor content in formalin-fixed, paraffin-embedded tissue can be generated using image analysis.
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PMID:Quantitation of estrogen and progesterone receptors by immunocytochemical and image analyses. 161 13

The prognostic significance of 16 factors was investigated in a series of 311 women with unilateral, invasive breast carcinoma without distant metastases (M0) and treated with mastectomy. The series consisted of 93% of such cases diagnosed histologically in the city of Turku, Finland, from 1980 to 1984. Mitotic count, histological and nuclear grades, extent of tumor necrosis, axillary nodal status (pN), tumor size (pT), estrogen and progesterone receptor (PR) contents, and S-phase fraction were the most powerful single factors (p = 0.0001 or less). Axillary node negative cancers with no or only spotty tumor necrosis (92% of all pN0 cases) were associated with a 96% 5-year survival rate corrected for intercurrent causes. Among the axillary node positive cases the combination of high PR content (greater than 60 fmol/mg protein) and a low mitotic count could identify a subgroup with a 96% 5-year corrected survival rate (25% of all pN+ cases). It is concluded that both pN0 and pN+ breast cancer contain identifiable subgroups with greatly different prognosis.
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PMID:Identification of subgroups with favorable prognosis in breast cancer. 162 48

125I-EGF (epidermal growth factor) binding assay was used in tumoral specimens concerning 303 clinical T1-T2, N0-N1 breast carcinoma diagnosed between May 1987 and October 1989. Binding assay for epidermal growth factor receptor (EGFR) was performed using single saturating concentration of 125I-EGF incubated with membrane preparations in the presence or absence of unlabelled EGF. A median value of 3 fmol EGF binding capacity per mg of membrane was obtained and then selected as the threshold value to define positive and negative EGFR tumour samples. According to this definition, 50.8% of the samples were EGFR positive. We noted an inverse relationship between the expression of EGFR and that of oestrogen receptor, and a decreased EGFR expression with tumour differentiation. With a rather short median follow-up (16 months), the multivariate analysis shows that progesterone receptor appears as the only powerful predictor of disease-free survival (P = 0.002), taking into account that 70% of the patients received an adjuvant medical treatment.
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PMID:Prognostic value of epidermal growth factor receptor in a series of 303 breast cancers. 162 73

To establish a model system for preclinical radioimmunotherapy studies, attempts were made to graft 16 different human breast carcinoma cell lines into BALB/c nu/nu(nude) mice. Nine produced serially transplantable tumors growing at a variable rate, whereas seven failed to do so. Conversely, three new cell lines were established in monolayer culture from transplantable human breast tumors in nude mice. Twelve selected tumors and their corresponding cell lines were characterized for DNA ploidy, % S-phase, and breast epithelial mucin expression by immunohistochemistry and flow cytometry. A wide diversity of these cellular characteristics were found in that each tumor was unique and distinct from the others. DNA ploidy differed among the tumors but was not affected by switching between in vitro to in vivo growth. Some tumors expressed similar levels of the breast mucin both in vitro and in vivo, whereas most expressed lower levels as transplantable tumors. There was a good correlation between immunohistochemical and flow cytometric determination of surface and cytoplasmic mucin expression, and with both techniques estrogen and progesterone receptor positive tumors had significantly higher levels of mucin expression than receptor negative tumors. These 12 transplantable breast tumors, with their corresponding cell lines, provide an excellent model system for testing radioimmunotherapy and other therapeutic reagents because they exhibit diverse phenotypic characteristics that represented a mini-population of breast cancer patients' tumors, allowing assessment of the effect of therapy when confronted with different breast tumors' genotype and phenotype.
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PMID:Development and characterization of breast carcinoma cell lines as in vitro and in vivo models for breast cancer diagnosis and therapy. 163 39

To investigate the relationship between the sex steroid receptor (estrogen receptor [ER] and progesterone receptor [PR]) status and the cell proliferation kinetics during the menstrual cycle in normal and neoplastic epithelium of the uterine cervix, immunohistochemical localization of ER, PR, and cell proliferation-associated antigen, Ki-67, was investigated in 35 normal cervical specimens, 3 condylomas, 26 cervical intraepithelial neoplasia (CIN) samples, and 22 invasive squamous carcinoma samples. The presence of human papillomavirus (HPV) DNA was also studied. In the normal cervix, basal cells were usually ER positive, PR negative, and Ki-67 negative throughout the menstrual cycle. Parabasal cells were ER positive and PR negative in the follicular phase, but ER negative and PR positive, and Ki-67 positive in the luteal phase, and Ki-67-positive cells increased in number in the luteal phase. In contrast, PR positivity was observed in the cells of condyloma (2 of 2 cases), CIN (19 of 26 cases), and invasive squamous carcinoma (13 of 22 cases) irrespective of the menstrual phase. Moreover, most neoplastic cells containing HPV DNA type 16/18 were ER negative, whereas several lesions containing HPV DNA type 31/33/35 were weakly ER positive. Many Ki-67-labeled cells were observed in the neoplastic lesions. These results suggest that reduced ER expression and increased PR expression are associated with the proliferation of normal cervical squamous epithelium, and this proliferation-related receptor status, which is probably induced by HPV infection, is usually expressed in neoplastic cervical squamous cells.
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PMID:Immunohistochemical analysis of estrogen receptors, progesterone receptors, Ki-67 antigen, and human papillomavirus DNA in normal and neoplastic epithelium of the uterine cervix. 165 7

Estrogen and progesterone receptors were immunohistochemically recorded from 426 cases of primary mammary carcinoma. Immunohistochemical detection was based on monoclonal antibodies to estrogen receptor (H222) and progesterone receptor (KD68). Immunohistochemical and biochemical tests were correlated to each other with significance (p less than 0.0001) for either receptor. Some of the histological parameters exhibited relationships with the immunohistochemical receptor status. Receptor positivity of lobular, mucoid, tubular, and papillary carcinomas was more frequent than that of ductal carcinoma, whereas that of medullary carcinoma fell below ductal cases. A straight forward correlation of statistical significance was found to exist between histological tumor grade and steroid hormone receptor status. Receptor positivity of carcinomas with sizeable stroma components proved to be more frequent than that of carcinomas with lower stroma levels. Steroid hormone receptors can be immunohistochemically identified from cytological specimens, as well, though some limiting factors are implied in the latter. Thirteen percent of fine-needle aspirates provided falsely negative steroid hormone receptor findings, as compared to histological biopsy. This problem was encountered primarily in cases of low receptor positivity and high stroma content of carcinoma, factors for which only minor amounts of cell material could be obtained from puncturing. Clinical follow-up checks and evaluation of survival data revealed the immunohistochemically determined steroid hormone receptor status to be of significant importance to prognostication (ER-ICA p less than 0.00001; PgR-ICA p = 0.004). The prognosis of patients with negative estrogen and progesterone receptors was found to be worse than that of patients with positive receptor status. These studies are likely to confirm immunohistochemical determination of steroid hormone receptors, using monoclonal antibodies, to be a reliable method of great prognostic importance.
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PMID:[Steroid hormone receptors in mammary carcinoma. Immunohistochemical detection and prognostic significance]. 165 32

Fifty-two human breast tumors were screened for the presence of DNA homology to mouse mammary tumor virus (MMTV) using molecularly cloned MMTV proviral genomic DNA probes and dot-blot hybridization. Seven patients were found to contain an entire provirus (gag, pol, env, and LTR positive at high stringency). Fifty percent (5/10) of patients having a first degree relative with breast carcinoma were found to have DNA homology to the gag-pol portion of the MMTV genome when hybridization and washing was performed at moderate (56C) stringency. Thirty-nine percent (7/18) of patients with any positive family history and 23 percent (8/34) of patients with a negative family history demonstrated homology under these parameters. Of the patients positive for gag-pol at moderate stringency, fewer had taken exogenous hormones than the sample group (20 percent vs 52 percent), more were parous (93 percent vs 68 percent), estrogen receptor positive (69 percent vs 48 percent), and male (13 percent vs 4 percent). At higher stringency (62C) no correlation to family history, hormone use or sex was detected, but positivity was noted among estrogen and progesterone receptor positive patients (67 percent vs 48 percent). Under lower stringency wash conditions, mismatched MMTV-related sequences are identified suggesting the existence of an endogenous gene with partial homology to MMTV. High stringency hybridization may identify a related retrovirus with significant homology to MMTV.
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PMID:Sequence homology of deoxyribonucleic acid to mouse mammary tumor virus genome in human breast tumors. 166 95

Two human cell lines (UACC-812 and 893), both containing significant amplification of the HER-2/neu gene, were established from biopsy specimens of breast carcinomas. One patient had Stage II breast carcinoma; the other had metastatic disease. Characterisation of these lines has revealed that both are highly aneuploid containing multiple clonal chromosome alterations, have doubling times near 100 h, and are oestrogen and progesterone receptor negative. Electron microscopy demonstrates that both lines contain numerous microvilli, cytoplasmic filaments, multivesicular bodies, and desmosomes. Immunoblot analysis for P-glycoprotein using the monoclonal antibody C219 was negative for both patient cell lines. These relatively rare cell lines may represent a useful model to investigate human breast carcinomas.
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PMID:Establishment of two new cell lines derived from human breast carcinomas with HER-2/neu amplification. 167 77

Immunocytochemical progesterone receptor (PR) assays employing two different monoclonal antireceptor antibodies (mPRi, JZB39) were compared with each other and with the dextran-coated charcoal assay (DCC) in human breast carcinoma. The immunocytochemical analyses were semiquantitatively scored (histoscore) based on relative staining intensity and the percentage of positively stained carcinoma cell nuclei. The immunocytochemically determined PR status agreed with that obtained by the DCC assay in 76% of the cases when the monoclonal antibody mPRi was used. The agreement was slightly better (82%) with the immunocytochemical assay using the JZB39 antibody. The semiquantitative histoscores correlated significantly with log-transformed cytosol PR concentrations in the DCC assay (mPRi, R = 0.543; JZB39, R = 0.618; P less than 0.0001 for both). The histoscores obtained with the mPRi and JZB39 antibodies were highly correlated with each other in adjacent frozen sections (R = 0.84, P less than 0.0001) the latter antibody giving somewhat higher histoscores. These results further validate the use of immunocytochemical PR assays for routine diagnostic purposes, especially when sufficient material is not available for DCC assays.
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PMID:Immunocytochemical detection of progesterone receptor in breast carcinoma. Comparison of two monoclonal antibodies. 168 43


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