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)

Adjuvant chemotherapy in breast cancer patients has had limited success, which is possibly because of lack of effect on non-proliferating cells accompanied by the emergence of drug-resistant cell clones. Since immunotoxins (ITs) are known to exert proliferation-independent cytotoxicity, we investigated the efficacy of systemically administered anti-carcinoma ITs in nude rat models, simulating micrometastatic disease. The monoclonal antibodies MOC31, BM7 and 425.3, which recognize epithelial glycoprotein 2, MUC-1 mucin and the epidermal growth factor receptor, chemically conjugated to Pseudomonas exotoxin A (PE), inhibited protein synthesis of the 2 breast cancer cell lines at concentrations of 0.3-0.4 ng/ml, except for BM7-PE, which was less efficacious (65 ng/ml). In the MA-11 model in nude rats, a single i. v. dose of 20 microg MOC31-PE prevented development of metastasis in the spinal cord in 11/19 (58%) of the animals. Similarly, 425.3-PE treatment gave 6/9 (66%) long-term survivors. In rats injected intracardially or intratibially with MT-1 cells, treatment with 425. 3-PE prevented metastasis in 4/10 (40%) and intratibial tumor growth in 17/18 (94%) of the rats. Importantly, an equimolar dose of free 425.3 (antibody) was ineffective, whereas PE alone was toxic. With BM7-PE, 5/17 (29%) cures were obtained in the intratibial model. The results demonstrate that systemic short-term treatment with non-toxic doses of the 3 ITs tested can effectively inhibit the development of experimental breast cancer metastasis and/or local tumor growth in bone. The results support the development of the ITs towards clinical evaluation for possible use as short-term adjuvant therapy in patients at high risk of early relapse.
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PMID:Systemic immunotoxin treatment inhibits formation of human breast cancer metastasis and tumor growth in nude rats. 1109 23

Mucin-1 (MUC-1), which is overexpressed in more than 90% of human breast cancers, is a potential target for immunotherapy. To develop a mouse model appropriate for the immunotherapy of human cancer, mouse mucin-1 (muc-1) fusion protein, containing ten tandem repeats, was made and used to immunize C3H/HeOuj mice, which supposedly have a high incidence of breast cancer. C3H/HeOuj mice were injected eight times with 5 microg oxidized mannan muc-1-glutathione-S-transferase (MMFP) with or without cyclophosphamide, which is used to increase cellular immunity. At 80 age weeks, only 12.1% (4 of 33) mice of the untreated C3H/HeOuj mice had mammary tumors. The reason for the low incidence of breast cancer in these mice is not known, but all the mammary tumors were MUC-1+ breast adenocarcinomas and were transplantable to C3H/HeOuj mice. The incidence was 11.4% (4 of 35) in mice injected with MMFP: 38.2% (13 of 34) in mice given cyclophosphamide; and 14.3% (2 of 14) in mice treated with glutathione-S-transferase. That is, cyclophosphamide increased the incidence of mammary tumors, and metastases were found in only these mice. Fewer tumors (6 of 34 or 17.6% compared with 13 of 34 or 38.2% with cyclophosphamide only) occurred in the group immunized with MMFP and cyclophosphamide. Mice immunized with MMFP had high levels of muc-1 antibodies and cellular immune responses (the frequency of the precursor of the cytotoxic Tlymphocyte cell was 1 of 40,000 to 1 of 100,000), which were not found in control groups. The occurrence of muc-1 immunity, particularly the presence of large amounts of anti-mucin-1 antibodies, had no effect on tumor incidence. Thus, the immunization with murine muc-1 reduced the tumor incidence in only cyclophosphamide-treated mice and led to strong muc-1 antibody production and to cellular responses. These findings have implications for human tumor immunotherapy in which strong antibody and weak cellular responses are to be expected and, indeed, have been found.
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PMID:Breast cancer in mice: effect of murine MUC-1 immunization on tumor incidence in C3H/HeOuj mice. 1121 Nov 44

Recently, a fully automated method has become commercially available to measure the MUC-1-associated antigen CA27.29. The present investigation was performed in order to compare CA27.29 and CA15.3 in a wide series of patients affected with breast cancer. Overall, 603 cases with breast cancer and 194 healthy controls were investigated. Patients were enrolled in 4 institutions, while assays were performed in one laboratory. CA27.29 was measured by the ACS:180 BR assay (Bayer Diagnostics) and CA15.3 by the AxSYM (Abbott Laboratories). An excellent correlation was found between the results obtained by the two methods. The two markers showed comparable results in healthy controls, with higher levels in post-menopausal than in pre-menopausal subjects. The markers were significantly higher in primary breast cancer than in controls. The areas under the receiver operating characteristics (ROC) curves of the two tests were comparable, but CA27.29 showed better sensitivity in cases with low antigen concentrations (below the cut-off point). Accordingly, when comparing each test in different stage categories, significance levels of the differences were higher for CA27.29 than for CA15.3 for all T categories versus healthy controls, for pT1 versus pT2, for all N categories versus healthy controls and for node-negative versus N1-3 patients. From the results of the present study, that has been performed on samples taken at diagnosis and prior to any treatment from the widest series of patients with primary breast cancer reported so far, we can draw the following conclusions: CA27.29 provides comparable results to CA15.3; CA27.29 seems more sensitive than CA15.3 to limited variations of tumour extension; however, it cannot help clinicians in distinguishing stage I patients from stage II patients. However, from the point of view of clinical decision making, CA27.29 provides comparable results to CA15.3. CA27.29 is therefore suitable for routine use in the management of patients with breast cancer.
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PMID:CA27.29: a valuable marker for breast cancer management. A confirmatory multicentric study on 603 cases. 1123 57

Radioimmunotherapy (RIT) is a promising approach for treating metastatic breast cancer. Initial clinical trials using 131I radioimmunoconjugates, and more recent studies employing 90Y, have demonstrated objective, although transient, antitumor effects in heavily pretreated patients with minimal toxicity. Antibodies targeting unique epitopes of epithelial glycoprotein mucin (MUC-1) on breast cancer cell surfaces that have been studied in patients include BrE-3 (murine and humanized) and m170 (murine). Both antibodies react with at least 90% of breast cancers. In these and other RIT trials, myelosuppression has been the dose-limiting toxicity. However, this toxicity has been successfully circumvented with the use of autologous peripheral blood stem cell transplantation, and recent clinical trials have escalated 90Y doses up to 50 mCi/m(2). The therapeutic index indicates that using these agents with stem cell support should deliver 9000 to 18000 rads to metastatic tumors. Development of improved chelates that are readily metabolized in the liver may reduce doses to this organ, projected to be next in line as dose-limiting. Combination therapy will be required to produce durable benefits in metastatic breast cancer. Low dose taxanes are synergistic with RIT in preclinical studies and when administered in the optimal sequence could sensitize tumor cells to the continuous low dose radiation delivered by RIT, without increasing toxicity. The addition of systemically administered tumor targeting radiation therapy using RIT as part of combined modality therapy may enhance the rate of complete response and, in patients with minimal metastatic disease, could lead to curative therapy.
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PMID:Systemic radiotherapy in metastatic breast cancer using 90Y-linked monoclonal MUC-1 antibodies. 1125 79

It has been reported that MUC-1 molecules devoid of the tandem repeat region (MUC-1/Y) are detected preferentially in carcinoma cells and are associated with their progression. However, its clinical significance is still unknown. We constructed a mouse colon adenocarcinoma cell line (MC-38) transduced with either MUC-1/Y cDNA defecting the tandem repeat region (Y-MC-38) or MUC-1/R cDNA containing ten tandem repeats (R-MC-38). RT-PCR of mRNAs derived from Y-MC-38 cells using the specific primers to MUC-1/Y mRNAs, proved the existence of 600 bp RT-PCR products generated only from MUC-1/Y mRNAs. DF3 and CA19-9 epitopes out of the MUC-1-related tumor-associated antigens, have been reported to be involved in the prognosis of cancer patients. We examined the expression of DF3 and CA19-9 epitopes on Y-MC-38 and R-MC-38 cells. Fluorescence-activated cell sorting (FACS) analysis of R-MC-38 and Y-MC-38 cells using two monoclonal antibodies against DF3 (mAb DF3) and CA19-9 (mAb CA19-9) epitopes revealed that R-MC-38 cells expressed DF3 but not CA19-9 [DF3(+)CA19-9(-)], while Y-MC-38 cells expressed CA19-9 but not DF3 [DF3(-)CA19-9(+)]. On Western blot, a 40 kDa protein product was recognized by mAb CA19-9 but not by mAb DF3 on cell lysates of Y-MC-38 cells, whereas a 70 kDa protein product was recognized by mAb DF3 but not by mAb CA19-9 on the cell lysates of R-MC-38. Further, we analyzed the expression of MUC-1/Y mRNAs by RT-PCR on various human cancer cell lines: the gastric cancer cell line AZ521, the pancreatic cancer cell lines PANC-1 and Capan-1, the gall bladder cell line GBK-1, the breast cancer cell line MCF-7, and the colon cancer cell lines HT-29 and Colo205. HT-29 and Capan-1 cells producing the 600 bp RT-PCR product, were positive for mAb CA19-9. These results demonstrate that CA19-9 epitope is produced only on MUC-1/Y core protein, suggesting that CA19-9 epitope may be a specific marker for MUC-1/Y protein.
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PMID:CA19-9 epitope a possible marker for MUC-1/Y protein. 1129 60

1-O-octadecyl-2-O-methyl-glycerophosphocholine (ET-18-OMe) is an analogue of the naturally occurring 2-lysophosphatidylcholine belonging to the class of antitumor lipids. Previously, we demonstrated that ET-18-OMe modulates cell-cell adhesion of human breast cancer MCF-7 cells. In the present study, we tested the effect of ET-18-OMe on adhesion, invasion and localisation of episialin and E-cadherin in MCF-7/AZ cells expressing a functional E-cadherin/catenin complex. The MCF-7/6 human breast cancer cells were used as negative control since their E-cadherin/catenin complex is functional in cells grown on solid substrate but not in suspension. The function of E-cadherin, a calcium-dependent transmembrane cell-cell adhesion and signal-transducing molecule, is disturbed in invasive cancers by mutation, loss of mRNA stability, proteolytic degradation, tyrosine phosphorylation of associated proteins and large cell-associated proteoglycans or mucin-like molecules such as episialin. Episialin, also called MUC1, is an anti-adhesion molecule that by its large number of glycosylated tandem repeats can sterically hinder the adhesive properties of other glycoproteins. ET-18-OMe inhibited the E-cadherin functions of MCF-7/AZ cells as measured by inhibition of fast and slow aggregation and by the induction of collagen invasion. These effects were enhanced by MB2, an antibody against E-cadherin and blocked by monoclonal antibodies (MAbs) 214D4 or M8 against episialin. ET-18-OMe had no influence on tyrosine phosphorylation of beta-catenin and the E-cadherin/catenin complex remained intact. Transcription, translation, protein turnover and cell surface localisation of episialin were not altered. ET-18-OMe induced finger-like extensions with clustering of episialin together with E-cadherin and carcinoembryonic antigen but not with occludin. In cells in suspension, ET-18-OMe caused a shift in the flow-cytometric profile of episialin toward a lower intensity for MCF-7/AZ cells. In contrast with MCF-7/AZ cells, the adhesion-deficient and noninvasive MCF-7/6 cells showed neither morphotypic changes nor induction of aggregation nor invasion in collagen I upon treatment with ET-18-OMe. Co-localisation of episialin with E-cadherin was rarely observed. We conclude that in the human breast cancer cells MCF-7/AZ, E-cadherin and episialin are key molecular players in the regulation of promotion and suppression of cell-cell adhesion and invasion.
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PMID:Alkyl-lysophospholipid 1-O-octadecyl-2-O-methyl- glycerophosphocholine induces invasion through episialin-mediated neutralization of E-cadherin in human mammary MCF-7 cells in vitro. 1130 87

MUC1 mucin is known to serve as a target molecule in the killing of breast cancer cells by cytotoxic T-lymphocytes (CTLs). We searched for a possible mechanism allowing tumour cells to escape from autologous CTLs. When the killing of breast cancer cells by autologous lymphocytes was examined in 26 patients with breast cancer, significant tumour cell lysis was observed in 8 patients, whereas virtually no autologous tumour cell lysis was detected in as many as 18 patients. In the patients who showed negligible tumour cell lysis, the autologous tumour cells expressed MUC1-related antigenic epitopes much more weakly than the tumour cells in the patients who exhibited strong cytotoxicity (significant statistically at P< 0.0005-0.0045), suggesting that the unresponsiveness of cancer cells to CTLs observed in these patients was mainly due to loss of MUC1 expression or modulation of its antigenicity. A breast cancer cell line, NZK-1, established from one of the cytotoxicity-negative patients, did not express MUC1 and was resistant to killing by CTLs, while control breast cancer cell lines expressing MUC-1 were readily killed by CTLs. Transfection of NZK-1 cells with MUC1 cDNA induced significant lysis by autologous T-lymphocytes. These results supported the importance of MUC1 mucin in autologous anti-tumour immunity, but suggested that the major escape mechanism of tumour cells from autologous T-lymphocytes is the loss and/or modulation of MUC1 antigenicity on tumour cells, which would limit the effectiveness of possible immunotherapy designed to target the MUC1 mucin.
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PMID:Modulation of MUC1 mucin as an escape mechanism of breast cancer cells from autologous cytotoxic T-lymphocytes. 1133 79

The fate of breast cancer patients is dependent upon elimination or control of metastases. We studied the effect of antibody-targeted liposomes containing entrapped doxorubicin (DXR) on development of tumours in two models of breast cancer, pseudometastatic and metastatic, in mice. The former used the mouse mammary carcinoma cell line GZHI, which expresses the human MUC-1 gene (L. Ding, E.N. Lalani, M. Reddish, R. Koganty, T. Wong, J. Samuel, M.B. Yacyshyn, A. Meikle, P.Y.S. Fung, J. Taylor-Papadimitriou, B.M. Longenecker, Cancer Immunol. Immunother. 36 (1993) 9--17). GZHI cells seed into the lungs of Balb/c mice following intravenous injection. The latter used the 4T1-MUC1 cell line, a MUC-1 transfectant of the mouse mammary carcinoma cell line 4T1, which metastasizes from a primary mammary fatpad (mfp) implant to the lungs (C.J. Aslakson, F.R. Miller, Cancer Res. 52 (1992) 1399--1405). B27.29, a monoclonal antibody against the MUC-1 antigen, was used to target sterically stabilized immunoliposomes (SIL[B27.29]) to tumour cells. In vitro, SIL[B27.29] showed high specific binding to both GZHI and 4T1-MUC1 cells. The IC(50) of DXR-loaded SIL[B27.29] was similar to that of free drug for GZHI cells. In the pseudometastatic model, mice treated with a single injection of 6 mg DXR/kg in DXR-SIL[B27.29] at 24 h after cell implantation had longer survival times than those injected with non-targeted liposomal drug. In the metastatic model, severe combined immune deficiency mice given weekly injectionsx3 of 2.5 mg DXR/kg encapsulated in either targeted or non-targeted liposomes were almost equally effective in slowing growth of the primary tumour and reducing development of lung tumours. Surgical removal of the primary tumour from mfp, followed by various chemotherapy regimens, was attempted, but removal of the primary tumour was generally incomplete; tumour regrowth occurred and metastases developed in the lungs in all treatment groups. DXR-SL reduced the occurrence of regrowth of the primary tumour, whereas neither targeted liposomal drug or free drug prevented regrowth. We conclude that monoclonal antibody-targeted liposomal DXR is effective in treating early lesions in both the pseudometastatic and metastatic models, but limitations to the access of the targeted liposomes to tumour cells in the primary tumour compromised their therapeutic efficacy in treating the more advanced lesions.
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PMID:Anti-MUC-1 immunoliposomal doxorubicin in the treatment of murine models of metastatic breast cancer. 1134 46

Human epithelial mucin, MUC-1, is commonly expressed in adenocarcinoma including 80% of breast cancers. erbB-2 is overexpressed in approximately 30% of breast cancers. Expression of MUC-1 and erbB-2 may be partially overlapping but discoordinate. Therefore, combined use of antibodies directed against these two antigens might increase the number of patients who benefit from immunotherapy. Monoclonal antibody (MAb) DF3 recognizes the MUC-1 tandem repeat. We investigated phagocytosis and cytolysis of cultured human breast cancer cells by monocyte-derived macrophages mediated by MAb DF3 and its bispecific antibody (BsAb) DF3xH22 with the second epitope directed against the Fc component of phagocytic cells. Purified monocytes from healthy donors were cultured with granulocyte macrophage colony-stimulating factor with or without IFN-gamma. antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC) assays were performed with these macrophages and MUC-1-expressing target cells (ZR75-1) in the presence of MAb DF3 and BsAb DF3xH22. ADCP was measured by two-color fluorescence flow cytometry using PKH2 (green fluorescent dye) and R-phytoerythrin (RPE) (red)-conjugated MAb against human CD14 and CD11b and was confirmed by confocal microscopy. ADCC was measured by (51)Cr release assay. Immunohistochemical staining studies of MUC-1 and erbB-2 were performed on 67 primary breast cancer tissues. Expression of MUC-1 and erbB-2 was partially overlapping but discoordinate in 67 consecutive breast cancers. Both MAb DF3 and BsAb DF3xH22 mediated ADCP. However, ADCP mediated by MAb DF3 was greater than that mediated by BsAb DF3xH22. ADCC as detected by (51)Cr release was not seen with either antibody. The addition of IFN-gamma to monocyte-derived macrophage cultures inhibited ADCP compared to granulocyte macrophage colony-stimulating factor alone. Given the partially overlapping but discoordinate expression of MUC-1 and erbB-2 in breast cancer, therapy directed toward both antigens should be considered. MAb DF3 and the BsAb DF3xH22, can effectively mediate phagocytosis of MUC-1-expressing target cells. Further investigations are needed to determine whether this antibody-induced phagocytosis results in long-term specific T-cell activation against MUC-1.
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PMID:Phagocytosis of breast cancer cells mediated by anti-MUC-1 monoclonal antibody, DF3, and its bispecific antibody. 1135 26

Human polymorphic epithelial mucin (PEM, MUC1) is a high molecular weight transmembrane glycoprotein expressed on the apical cell surface of glandular epithelium and is over-expressed and hypo-glycosylated in adenocarcinomas. The extracellular part of the molecule consists mainly of a variable number of 20 amino acid repeats that contain cryptic epitopes exposed in malignancy. The objective of our study was to determine whether humanized MUC1 MAbs and Abs induced by vaccination of breast cancer patients with MUC1 peptides can effect an antibody-dependent cell-mediated cytotoxicity (ADCC). An in vitro assay has been set up in which the breast tumor cell line ZR-75-1 is used as target and PBMC of healthy donors as effector cells. Different target and effector cells, as well as various MUC1 MAbs were tested to optimize the efficacy of the in vitro assay. The humanized MAb HuHMFG-1, which recognizes the PDTR sequence in the MUC1 tandem repeat, induced a strong cell-mediated cytotoxicity. Nine MUC1-expressing tumor cell lines, including 3 bone marrow-derived cell lines, as well as 2 MUC1-transfected cell lines were susceptible to different extent to MUC1 Ab-dependent killing. Large variations in the killing capacity of PBMC from healthy donors were found. The NK cells were the essential effector cells for the MUC1 Ab-dependent killing. Plasma samples with induced high levels of MUC1 Ab were obtained from breast cancer patients repeatedly immunized with a KLH-conjugated 33-mer or 106-mer MUC1 tandem repeat. Pre- and post-vaccinated plasma samples of these patients were compared in the ADCC assay and it could be clearly demonstrated that the induced MUC1 Abs can effect tumor cell killing. MUC1 Ab-dependent cell-mediated tumor cell killing may occur in vivo and the ADCC assay can be applied to monitor MUC1 vaccination trials.
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PMID:Antibody-dependent cell-mediated cytotoxicity can be induced by MUC1 peptide vaccination of breast cancer patients. 1139 28

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