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)

Using immunohistochemistry and the monoclonal antibody C219 we have investigated P-glycoprotein expression in 26 locally advanced breast cancers. Twenty four patients had received four cycles of chemotherapy (mitozantrone, mitomycin-C and methotrexate) prior to mastectomy; two received tamoxifen. Twelve tumours exhibited an objective response to the chemotherapy. A background pattern of isolated weakly positive (1+) stromal staining (myofibroblast) was observed in seven tumours, two of which had been treated by tamoxifen alone. Two of the tumours treated by induction chemotherapy showed positive staining (1+) within a very small number of isolated tumour cells (maximum of three) and macrophages. The significance of this staining is not clear although C219 may simply be cross reacting with myosin. We have failed to demonstrate a clear clinical utility for C219 in breast cancer, particularly regarding the identification of patients in whom MDR chemotherapy be avoided once metastases develop.
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PMID:P-glycoprotein expression in locally advanced breast cancer treated by neoadjuvant chemotherapy. 135 61

To assess chemotherapeutically induced myocardial damage, myosin-specific antibody scans and ejection fraction measurements were performed in 32 patients with breast cancer and in 9 patients with other tumours. All patients had received chemotherapy including anthracyclines. The ejection fraction decreased by less than or equal to 10% in 14 of 41 (34%) patients after chemotherapy. Antimyosin uptake in the myocardium was observed in 38 of 41 (92%) patients after chemotherapy. Antimyosin uptake was quantified by means of a heart-to-lung ratio, revealing a correlation between the degree of antimyosin uptake in the myocardium and the cumulative dose of anthracycline. Patients with a decreased ejection fraction showed more intense antimyosin uptake, indicating more severe myocardial damage. A higher degree of antimyosin uptake was found in 17 breast cancer patients treated with doxorubicin compared with 15 patients treated with mitoxantrone. We conclude that antimyosin studies provide a sensitive, non-invasive method to monitor myocardial damage in patients treated with anthracyclines. Antimyosin uptake in the myocardium precedes ejection fraction deterioration. This technique may be helpful in the early identification of patients at risk of congestive heart failure during chemotherapy including anthracyclines.
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PMID:Assessment of anthracycline-induced myocardial damage by quantitative indium 111 myosin-specific monoclonal antibody studies. 174 3

Immunomorphologic study of 29 breast cancer cases using monoclonal antibodies to proteins of intermediate filaments shown to differentiate the lining epithelium from myoepithelium in the non-proliferating epithelial structures of the mamma, has shown the cells in the majority of tumours (according to the International WHO Classification defined as infiltrating ductal, lobular, and tubular cancer forms) to contain prekeratin (PK) C12, specific for normal lining epithelium, but not for the myoepithelium. In cases of cancer with chondroid metaplasia (a malignant variant of the so-called "mixed tumour") the cells contained PK E3, vimentin and structural myosin, normally specific for myoepithelium. The cell heterogenicity in PK C12 content or its absence noted in the infiltrating cancers with predominance of a solid component can indicate a high degree of tumour anaplasia. It is concluded that usage of monoclonal antibodies to PK C12, invariably found in the cells of fibrotic invasion foci, can be a useful indicator for early diagnosis of infiltrative tumour growth.
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PMID:[Immunohistochemical research on human breast tumors using monoclonal antibodies to intermediate filament proteins. Cancer of the breast]. 353 48

Urokinase-type plasminogen activator (uPA) activates the mitogen activated protein (MAP) kinases, extracellular signal-regulated kinase (ERK) 1 and 2, in diverse cell types. In this study, we demonstrate that uPA stimulates migration of MCF-7 breast cancer cells, HT 1080 fibrosarcoma cells, and uPAR-overexpressing MCF-7 cells by a mechanism that depends on uPA receptor (uPAR)-ligation and ERK activation. Ras and MAP kinase kinase (MEK) were necessary and sufficient for uPA-induced ERK activation and stimulation of cellular migration, as demonstrated in experiments with dominant-negative and constitutively active mutants of these signaling proteins. Myosin light chain kinase (MLCK) was also required for uPA-stimulated cellular migration, as determined in experiments with three separate MLCK inhibitors. When MCF-7 cells were treated with uPA, MLCK was phosphorylated by a MEK-dependent pathway and apparently activated, since serine-phosphorylation of myosin II regulatory light chain (RLC) was also increased. Despite the transient nature of ERK phosphorylation, MLCK remained phosphorylated for at least 6 h. The uPA-induced increase in MCF-7 cell migration was observed selectively on vitronectin-coated surfaces and was mediated by a beta1-integrin (probably alphaVbeta1) and alphaVbeta5. When MCF-7 cells were transfected to express alphaVbeta3 and treated with uPA, ERK was still phosphorylated; however, the cells did not demonstrate increased migration. Neutralizing the function of alphaVbeta3, with blocking antibody, restored the ability of uPA to promote cellular migration. Thus, we have demonstrated that uPA promotes cellular migration, in an integrin-selective manner, by initiating a uPAR-dependent signaling cascade in which Ras, MEK, ERK, and MLCK serve as essential downstream effectors.
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PMID:Myosin light chain kinase functions downstream of Ras/ERK to promote migration of urokinase-type plasminogen activator-stimulated cells in an integrin-selective manner. 1040 67

Both epidemiological and experimental studies indicate that ethanol is a tumor promoter and that chronic ethanol exposure enhances metastasis of breast cancer cells, and with an in vitro model (T47D human breast cancer cells), we have previously demonstrated that ethanol exposure stimulated the migration of breast cancer cells. In the present study, differential display reverse transcription polymerase chain reaction was used to identify ethanol-responsive genes in T47D cells. Three differentially displayed, ethanol-responsive gene fragments were identified, and their expression was confirmed by Northern blot hybridization. Sequence analysis revealed that one cDNA fragment represented the myosin alkali light chain (MLC 1sm) of human smooth muscle. The expression of MLC 1sm was found to be significantly higher in breast cancer cells than in normal mammary epithelial cells. With T47D cells, ethanol induced an additional duration- and concentration-dependent up-regulation of MLC 1sm. At 400 mg/dl, an ethanol-mediated increase was evident at 6 h (55% increase), peaked at 24 h (2.7-fold increase) following exposure, and diminished thereafter. At pharmacologically relevant concentrations (e.g., 100 mg/dl), ethanol produced a significant increase of MLC 1sm expression, and progressively higher ethanol concentrations resulted in more up-regulation. The half-life of MLC 1sm mRNA was not altered, however, the transcription rate of MLC 1sm was significantly increased by ethanol. MLC is a structural component of the cytoskeleton of eukaryotic cells, and it plays critical roles in the regulation of cell shaping, movement, and growth. Thus, ethanol-mediated up-regulation of MLC may be an underlying molecular mechanism for its tumor promoting effect.
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PMID:Up-regulation of transcription of smooth muscle myosin alkali light chain by ethanol in human breast cancer cells. 1135 Dec 66

Experimentally elevated levels of S100A4 induce a metastatic phenotype in benign mammary tumour cells in vivo. In humans, the presence of S100A4 in breast cancer cells correlates strongly with reduced patient survival. Potential interacting binding partners for S100A4 have now been examined using an optical biosensor. There was significant interaction of S100A4 with non-muscle myosin and p53, but not with actin, tropomyosin or tubulin. The results suggest that myosin and p53 are likely to be intracellular targets of S100A4. S100A4 had a greater affinity for wild-type or mutant arg-175-his p53 than for non-muscle myosin. The results suggest that S100A4 might induce metastasis by influencing the function of p53 as well as through its interaction with myosin and that any mechanism is independent of the mutational status of p53.
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PMID:Binding to intracellular targets of the metastasis-inducing protein, S100A4 (p9Ka). 1152 29

Barrier dysfunction of pulmonary endothelial monolayer is associated with dramatic cytoskeletal reorganization, activation of actomyosin contractility, and gap formation. The linkage between the microtubule (MT) network and the contractile cytoskeleton has not been fully explored, however, clinical observations suggest that intravenous administration of anti-cancer drugs and MT inhibitors (such as the vinca alkaloids) can lead to the sudden development of pulmonary edema in breast cancer patients. In this study, we investigated the crosstalk between MT and actomyosin cytoskeleton and characterized specific molecular mechanisms of endothelial cells (EC) barrier dysfunction induced by MT inhibitor nocodazole (ND). Our results demonstrate that MT disassembly by ND induced rapid decreases in transendothelial electrical resistance (TER) and actin cytoskeletal remodeling, indicating EC barrier dysfunction. These effects involved ND-induced activation of Rho GTPase. Rho-mediated activation of its downstream target, Rho-kinase, induced phosphorylation of Rho-kinase effector EC MLC phosphatase (MYPT1) at Thr(696) and Thr(850) resulting in MYPT1 inactivation. Phosphatase inhibition leaded to accumulation of diphospho-MLC, which induced acto-myosin polymerization, stress fiber formation and gap formation. Inhibition of Rho-kinase by Y27632 abolished ND-induced MYPT1 phosphorylation, MLC phosphorylation, and stress fiber formation. In addition, MT preservation via the MT stabilizer paclitaxel, Rho inhibition (via C3 exotoxin, or dominant negative (DN)-Rho, or DN-Rho-kinase) attenuated ND-induced TER decreases, stress fiber formation and MLC phosphorylation. Collectively, our results demonstrate a leading role for Rho-dependent mechanisms in crosstalk between the MT and actomyosin cytoskeleton, and suggest Rho-kinase and MYPT1 as major Rho effectors mediating pulmonary EC barrier disruption in response to ND-induced MT disassembly.
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PMID:Microtubule disassembly induces cytoskeletal remodeling and lung vascular barrier dysfunction: role of Rho-dependent mechanisms. 1528 Oct 89

Elevated levels of the calcium-binding regulatory protein, S100A4, have been shown to be causative of a metastatic phenotype in models of cancer metastasis and to be associated with reduced patient survival in breast cancer patients. Recombinant S100A4 protein interacts in vitro in a calcium-dependent manner with the heavy chain of non-muscle myosin isoform A at a protein kinase C phosphorylation site. At present, the mechanism of metastasis induction by S100A4 in vivo is almost completely unknown. The binding of S100A4 to a C-terminal recombinant fragment of non-muscle myosin heavy chain in living HeLa cells has now been shown using confocal microscopy, fluorescence lifetime imaging microscopy and time-correlated single-photon counting. The association between S100A4 and non-muscle myosin heavy chain was studied by determining fluorescence resonance energy transfer-derived changes in the fluorescence lifetime of enhanced cyan fluorescent protein fused to S100A4 in the presence of a recombinant fragment of the C-terminal region of non-muscle myosin heavy chain (rNMMHCIIA) fused to enhanced yellow fluorescent protein. There was no interaction between the non-muscle myosin heavy chain fragment and a calcium-binding-deficient mutant of S100A4 protein which has been shown to be defective in the induction of metastasis in model systems in vivo. The results demonstrate, for the first time, not only direct interaction between S100A4 and a target rNMMHCIIA in live mammalian cells, but also that the interaction between S100A4 and the non-muscle myosin heavy chain in vivo could contribute to the mechanism of metastasis induction by a high level of S100A4 protein.
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PMID:Interaction of metastasis-inducing S100A4 protein in vivo by fluorescence lifetime imaging microscopy. 1528 39

Increased levels of the homodimeric calcium-binding protein, S100A4, have been shown to cause a metastatic phenotype in at least three independent model systems of breast cancer and its presence in carcinoma cells has been shown to be associated with a reduction in the survival of patients suffering from a range of different cancers. S100A4 has been shown to interact in vitro with another member of the S100 family of proteins, S100A1. The purpose of the present study was to find out whether S100A1 could affect S100A4 function. Fluorescence resonance energy transfer was used to show the interaction of S100A4 and S100A1 in living cells and the binding affinities between S100A4 and S100A1 were determined using a biosensor. S100A1 reduced the S100A4 inhibition of nonmuscle myosin A self-association and phosphorylation in vitro. S100A1 reduced S100A4 induced motility and growth in soft agar and metastasis in vivo. The results show for the first time that interactions between different S100 proteins can affect cancer-related activity, and that the presence of S100A1 protein in carcinoma cells might modulate the effect of S100A4 on their metastatic abilities.
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PMID:Mutually antagonistic actions of S100A4 and S100A1 on normal and metastatic phenotypes. 1560 82

Nodular mucinosis is an extremely rare breast lesion. This benign mass usually presents clinically as a poorly circumscribed, subareolar, myxoid mass in young female patients. We report a case of this rare breast lesion and discuss its clinical, radiologic, and histopathologic features. A 21-year-old white woman presented with a mass in the left breast of 6 months' duration. She had never been pregnant or had any history of breast feeding, surgery, trauma, or use of exogenous hormones or a family history of breast cancer. Clinical breast examination demonstrated a 1 cm "rubbery" mass directly under and continuous with the left nipple. The skin that covered the mass had an edematous and irregular appearance without erythema or drainage from the nipple. Ultrasonography demonstrated a 1-cm, nonintraductal, circumscribed, homogeneous, isoechoic mass that was continuous or part of the base of the left nipple. The mass was smooth, with a thin echogenic rim. Doppler flow showed some vascularity. These findings suggested a benign breast lesion, including a fibroadenoma or nipple adenoma. Despite reassurance, the patient desired excision of the lesion. Gross examination revealed a nodular, rubbery-firm, ovoid, pink, polypoid mass that measured 1.5 x 0.9 x 0.8 cm. Microscopic examination showed a well-circumscribed tumor with a nodular appearance, which consisted of an accumulation of pink myxoid tissue and contained spindle cells with bland-appearing nuclei, no mitosis, and mild cellularity. The pink myxoid tissue was stained with Hale colloidal iron and Alcian blue. The Alcian blue stain was removed by pretreatment with hyaluronidase. The spindle cells stained with vimentin and smooth muscle actin; however, they did not express smooth muscle myosin or cytokeratin. This report presents and discusses the pathologic, ultrasonographic, and clinical findings of this rare entity.
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PMID:Nodular mucinosis of the breast: a case report with pathologic, ultrasonographic, and clinical findings and review of the literature. 1573 51


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