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)

The progesterone receptor (PR) was partially purified from T47D human breast cancer cells by sequential chromatography on phosphocellulose, heparin-Sepharose, and DNA-cellulose. Heparin-Sepharose chromatography resulted in an efficient conversion of the receptor to a DNA-binding form (activation) since more than 85% of the 3H-R5020 labeled eluate from heparin-Sepharose was retained on DNA-cellulose and since the cytosolic 8S receptor was converted to a 4S moiety after chromatography on heparin-Sepharose. The 3H-R5020 labeled human PR eluted from DNA-cellulose as a single symmetrical peak at 0.2 M NaCl; after photoaffinity labeling and sodium dodecyl sulfate-polyacrylamide gel electrophoresis, this species was shown to consist of about equal amounts of two proteins of Mr approximately equal to 96,000 and 120,000 (the so called A- and B-subunits, respectively). This partially purified receptor preparation (SA 490 pmol/mg protein) did not contain any glucocorticoid receptor (GR) as shown by immunoblotting with a monoclonal antirat GR antibody that cross-reacts with the human GR. Therefore, this preparation was used to compare the specific DNA-binding properties of the human PR with those of the purified rat GR. The human PR bound specifically to the promoter region of mouse mammary tumor virus (MMTV) at a molar ratio between receptor and DNA similar to the molar ratio between GR and DNA needed for binding of rat GR to MMTV, indicating that the PR was purified in a biologically active form.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Unspecific and sequence-specific deoxyribonucleic acid binding of the partially purified human progesterone receptor. 284 63

Thrombospondin is an adhesive glycoprotein that promotes breast cancer cell adhesion to human vascular endothelial cells (Incardona et al., 1995). In this study, we have identified the molecular domains of thrombospondin that mediate its binding to specific receptors on the human breast adenocarcinoma cell line, MDA-MB-231. Two recombinant fragments from the amino-terminus (TSPN18 and TSPN28), and the fusion proteins of the type 1 and type 2 repeats of human thrombospondin, inhibited binding of radiolabeled thrombospondin to MDA-MB-231 cells in suspension by 40-60% at 50 micrograms/ml whereas the type 3 repeat, carboxy-terminus and unfused glutathione-S-transferase as well as the synthetic peptide Gly-Arg-Gly-Asp-Ser (500 micrograms/ml) had little or no effect. Heparin and various glycosaminoglycans as heparan sulfate, chondroitin sulfates A, B or C, and fucoidan inhibited thrombospondin binding to MDA-MB-231 cells by more than 60% whereas dextran sulfate had only little effect. Treatment of cells with heparitinase, chondroitinase ABC, and hyaluronidase, but not with neuraminidase, induced 30-50% inhibition of thrombospondin binding suggesting the participation of both heparan sulfate and chondroitin sulfate cell surface-associated molecules. Inhibition of proteoglycan sulfation by chlorate or inhibition of glycosaminoglycan chain formation by two beta-D-xylosides also led to a substantial inhibition of thrombospondin binding. Our results indicate that several domains within the thrombospondin molecule, namely the amino-terminus, type 1 and type 2 repeats, participate in its binding to specific receptors bearing sulfated glycosaminoglycans on MDA-MB-231 cells. Biological assays have indicated that, in addition to these domains, the peptide Gly-Arg-Gly-Asp-Ser inhibited MDA-MB-231 cell attachment to thrombospondin suggesting that the last type 3 repeat of the molecule may also contribute to its cell adhesive activity.
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PMID:Heparin-binding domain, type 1 and type 2 repeats of thrombospondin mediate its interaction with human breast cancer cells. 889 89

Proteoglycans (PG) are complex sulphated macromolecules composed of linear polysaccharide chains of glycosaminoglycans (GAG) covalently attached to a core protein. These GAG chains contain sulphate groups at various positions, giving them a high density of negative charges, and allowing them to interact with extracellular matrix molecules, including various growth factors. In the developing mammary gland, sulphated proteoglycans participate in morphogenesis and interact with extracellular matrix components in order to constitute a functional matrix. In breast pathogenesis, qualitative or quantitative changes in PG may have important consequences on cell proliferation and/or differentiation. Thus, several studies showed large variations in the nature and distribution of PG/GAG in breast cancer. Accumulation of chondroitin sulfate proteoglycans was described in the stromal compartment of mammary biopsy sections, and content in heparan sulfate proteoglycans, which were more specifically distributed in the epithelial compartment, increased with the level of malignancy and invasiveness of breast cancer tissues. Furthermore, heparan sulfate proteoglycans seem to be involved in control of the growth-promoting activity of numerous growth factors such as fibroblast growth factors also named Heparin-Binding Growth Factors (HBGF). The implication of PG in growth factor activity suggest that PG may have prognostic value in breast cancer. In future, structural studies into the specific HS-sequences involvement in growth factors binding could allow the development of new antiproliferative strategies.
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PMID:[Proteoglycans and breast cancer]. 929 79

Heparin/heparan sulfate interacting protein (HIP) is a recently identified protein expressed by many normal epithelia and epithelial cell lines. In the present study, we examined expression and potential functions of this protein in a series of human breast cancer cells and in sections of normal and malignant human breast tissue. Four of the five breast cancer cell lines studied (MCF-7, T-47D, MDA-MB468, and BT-549) expressed HIP protein and mRNA at similar levels. In contrast, MDA-MB-231 cells failed to display reactivity with HIP-specific probes in any assay. Cell aggregation assays and cell surface antibody binding studies demonstrated that HIP was expressed on the cell surface. However, HIP expression did not correlate with the number of cell surface [3H]heparin (HP) binding sites. The K(Dapp)s for cell surface HP binding sites were similar in all breast cancer cell lines studied and ranged from 112 to 298 nM. In contrast, cell surface HP binding capacity varied greatly, ranging from 2.3 x 10(5) (MDA-MB-231 and MDA-MB-468) to 99 x 10(5) sites/cell (BT-549). All cell lines tested displayed the ability to bind to a heparan sulfate (HS)-binding synthetic peptide motif of HIP in a HP-inhibitable fashion. Binding to this motif was not inhibited by other glycosaminoglycans including hyaluronic acid, chondroitin sulfates, or keratan sulfate. Furthermore, cell binding to HIP peptide was almost completely lost when intact cells were predigested with heparinases but not chondroitinases. Cell surface HS from breast cancer cells as well as normal human breast epithelia binded to HIP peptide in a HP-inhibitable fashion, demonstrating the ability of these cell surface components to directly interact. HIP was detected in both normal breast epithelia and breast tumors in situ. It is suggested that HIP mediates aspects of HS-dependent interactions of both normal and malignant breast epithelia with other cells and extracellular matrix components.
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PMID:Heparin/heparan sulfate interacting protein expression and functions in human breast cancer cells and normal breast epithelia. 937 17

The present study was designed to test the hypothesis that rhPF4 binds with high specificity to the neovasculature of breast cancer carcinoma. To achieve this goal, we used intravital microscopy to study the binding characteristics of systemically injected fluorescently labeled rhPF4 (FITC-rhPF4) to the microvasculature of dorsal skinfold chambers in nude mice implanted with tumor spheroids prepared from the human breast cancer cell line MCF-7. Our results show that intravenously as well as intra-arterially injected FITC-rhPF4 exclusively labeled, with high intensity and specificity, the endothelium of the breast cancer induced neovasculature. Only on rare occasions (0.7 +/- 1.5 site per cm2 skinfold), short (37 +/- 48 microns) intense labeled sites were found in the normal vasculature of the skinfold. Heparin could displace most of the label if injected within 10 min after the rhPF4-injection, but not 30 min after. In conclusion, our results show that rhPF4 preferentially binds to regions of active angiogenesis in vivo, supporting the concept of using rhPF4 conjugates to target tumors in cancer patients. Certain rhPF4 conjugates could have applications as imaging agents, with potential utility in identification, screening, detection, prognosis or staging of breast cancer and other cancers. Other similar conjugates, bearing therapeutic isotopes or toxins might be useful in selective treatment strategies.
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PMID:Recombinant platelet factor 4, an angiogenic marker for human breast carcinoma. 989 42

The European Consensus Conference has assessed the risk for thrombotic complications for most women undergoing gynecologic surgery and found it to be moderate. Nonetheless, it is important to analyze a patient's individual risk before surgery so that appropriate thrombosis prophylaxis can be given if increased risk is determined. Malignancy accounts for most thrombotic complications among gynecologic patients. Patients with known malignancies should receive prophylaxis during surgery, and some patients with breast cancer should receive prophylaxis during chemotherapy. Heparin, and low-molecular-weight heparin in particular, may favorably influence the outcome of cancer in some patients and treatment with these agents is currently under investigation in a number of trials as a new approach to anticancer therapy.
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PMID:Antithrombotic therapy in gynecologic surgery and gynecologic oncology. 1100 39

The soluble form of the syndecan-1 heparan sulfate proteoglycan acts as a tumor suppressor molecule that inhibits growth and induces apoptosis of some cancer cell lines in vitro. Analogs of syndecan-1 were produced by carbodiimide (EDAC) conjugation of glycosaminoglycan (GAG) chains to a protein scaffold, thereby generating synthetic proteoglycans that were evaluated for anticancer properties. Surprisingly, when analyzing activities of the controls, we discovered that EDAC modified GAG chains inhibit myeloma cell viability even in the absence of protein. Here, we describe the production and the activities of these novel molecules called neoglycans. The GAG chains heparin and chondroitin sulfate (CS) were exposed to EDAC to generate the neoglycans neoheparin and neoCS, respectively. Heparin and CS in the absence of EDAC modification have no effect or a slight growth promoting effect on cancer and normal cell lines. However, neoheparin and neoCS substantially reduce cell viability by induction of apoptosis of myeloma and breast cancer cells in vitro. NeoCS when injected directly into breast tumors growing in nude mice reduces or abolishes their growth without causing apparent toxicity to the adjacent normal tissue. The neoglycans need not be continuously present in cell cultures because a short pulse exposure is sufficient to reduce cell viability. NeoCS fractions purified by size exclusion chromatography reduce myeloma cell viability, confirming the specificity of neoglycan activity. Collectively, the results of this study demonstrate the anticancer activities of this new class of GAG chain-based molecules and provide the foundation for future development of neoglycans as novel therapeutic agents.
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PMID:Neoglycans, carbodiimide-modified glycosaminoglycans: a new class of anticancer agents that inhibit cancer cell proliferation and induce apoptosis. 1209 81

Hematoma and bruising (sugillation) are frequent problems after operations for primary breast cancer. In the present study we evaluated the influence of various methods of perioperative thromboembolic prophylaxis on the postoperative incidence of hematoma and suggilation. From June 1994 through August 1996, a series of 425 patients consecutively operated on for primary breast cancer were included. Thromboembolic prophylaxis was low-molecular-weight heparin (LMWH) in 310 patients and thigh-long graded compression (TED) stockings in 102 patients. Postoperative complications including deep vein thrombosis, pulmonary embolism, wound hematoma, and sugillation were recorded, and 17 variables with a potential influence on complications were analyzed by logistic regression analysis. Heparin prophylaxis compared to prophylaxis with TED stockings was significantly and independently associated with postoperative hematoma [odds ratio (OR) 3, 13; 95% confidence interval (CI) 1.38-7.13] or sugillation (OR 3.34; 95% CI 1.93-5.78). No clinically overt thromboembolic complications were diagnosed. After operations for breast cancer we found that LMWH was significantly associated with postoperative hematoma and sugillation compared to TED stockings for perioperative thromboembolic prophylaxis.
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PMID:Thromboembolic prophylaxis as a risk factor for postoperative complications after breast cancer surgery. 1536 41

The metastatic breast cancer cell line, 4T1, abundantly expresses the oligosaccharide sialylated Lewis x (sLe(x)). SLe(x) oligosaccharide on tumor cells can be recognized by E- and P-selectin, contributing to tumor metastatic process. We observed that both selectins reacted with this cell line. However, contrary to the E-selectin reactivity, which was sLe(x) dependent, P-selectin reactivity with this cell line was sLe(x)-independent. The sLe(x)-Neg variant of the 4T1 cell line with markedly diminished expression of sLe(x) and lack of sLe(a), provided a unique opportunity to characterize P-selectin ligands and their contribution to metastasis in the absence of overlapping selectin ligands and E-selectin binding. We observed that P-selectin binding was Ca(2+)-independent and sulfation-dependent. We found that P-selectin reacted primarily with cell surface chondroitin sulfate (CS) proteoglycans, which were abundantly and stably expressed on the surface of the 4T1 cell line. P-selectin binding to the 4T1 cells was inhibited by heparin and CS glycosaminoglycans (GAGs). Moreover, Heparin administration significantly inhibited experimental lung metastasis. In addition, the data suggest that surface CS GAG chains were involved in P-selectin mediated adhesion of the 4T1 cells to murine platelets and human umbilical vein endothelial cells. The data suggest that CS GAGs are also the major P-selectin-reactive ligands on the surface of human MDA-MET cells. The results warrant conducting clinical studies on the involvement of cell surface CS chains in breast cancer metastasis and evaluation of various CS types and their biosynthetic pathways as target for development of treatment strategies for antimetastatic therapy of this disease.
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PMID:Chondroitin sulfate glycosaminoglycans as major P-selectin ligands on metastatic breast cancer cell lines. 1715 73

Coagulation activation appears to play a role in tumor progression. Low-molecular-weight heparin (LMWH) may influence tumor growth and LMWHs have been shown to beneficially influence tumor response to chemotherapy. In a phase II study using docetaxel plus enoxaparin in 25 patients with advanced breast cancer, fibrin monomer, transforming growth factor-beta 1 (TGF-beta(1)) and response rates were evaluated. Enoxaparin was administered at a daily dose of 0, 5 or 1.0 mg/kg and docetaxel at 35-45 mg/m(2) once weekly. Nine patients achieved a partial response (36%) and nine patients (36%) had stable disease. The median time to progression was 11.5 weeks (range 5-51 weeks), and 16 weeks combining patients with partial remission and stable disease. One major bleed occurred. Patients with partial remission had a significant decrease of TGF-beta(1) and fibrin (P < 0.05). A significant correlation between TGF-beta(1) and fibrin monomer was also seen in all subgroups independent of clinical response. The most frequent toxicities were granulocytopenia, asthenia, transient peripheral edema and temporary hot flushes. In conclusion, docetaxel plus enoxaparin was quite active and well tolerated in patients with advanced breast cancer. These preliminary data suggest further clinical research using chemotherapy plus enoxaparin as an antitumor therapy in advanced breast cancer is warranted.
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PMID:Combining chemotherapy and low-molecular-weight heparin for the treatment of advanced breast cancer: results on clinical response, transforming growth factor-beta 1 and fibrin monomer in a phase II study. 1758 15


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