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)

G-proteins are essential in signal transduction pathways. A G-protein alpha subunit termed G alpha 16 was found to be exclusively expressed in hematopoietic cell lines. In cells derived from patients, G alpha 16 expression has been detected in progenitor- and pre-B ALL cells and also in peripheral blood stem cells (PBSC). In this study, we analyzed G alpha 16 expression using a RT-PCR technique by testing elutriated blood cells from normal donors, PBSC from breast cancer patients and bone marrow or peripheral blood cells from acute leukemia patients. Both of two ALL patients and 15/16 AML patients expressed G alpha 16. In elutriation experiments, G alpha 16 expression was found in fractions containing the highest number of precursor cells but was absent in mature T and B cell fractions. In addition, CD34-enriched PBSC were positive for G alpha 16 expression. Further in vitro experiments using the cell line KG1 showed that G alpha 16 expression was not affected by the growth inhibiting hemoregulatory peptide pEEDCK which has a sequence homology present within G alpha 16. Taken together, these data demonstrate that G alpha 16 is expressed in various normal and malignant hematopietic progenitors but not in their differentiated counterparts. G alpha 16 could play a vital role in signal transduction pathways controlling proliferation in early normal and malignant hematopoiesis.
Leukemia 1996 Jul
PMID:Expression of G alpha 16, a G-protein alpha subunit specific for hematopoiesis in acute leukemia. 868 89

The expression of transcripts of cytokines of the interleukin-6 (IL-6) family has been examined in human breast tumors, breast cancer cell lines, and adipose stromal cells, by means of reverse transcription polymerase chain reaction amplification. Of the six breast tumor samples examined, all expressed transcripts encoding IL-6 and Leukemia Inhibitory Factor (LIF). Four of the samples also expressed transcripts for oncostatin M (OSM) and IL-11, and three expressed the IL-6 receptor. Adipose stromal cells expressed IL-6, IL-11 and LIF, but not the IL-6 receptor, consistent with previous conclusions that IL-6 activity in these cells required addition of IL-6 soluble receptor. In the case of T47D cells, expression of IL-11 protein was confirmed by immunotitration. Moreover, in these cells, expression of IL-11 transcripts was induced 3-fold by addition of estradiol to the culture medium. These results add credence to our previous proposal that breast cancer development is regulated in part by local autocrine and paracrine mechanisms via epithelial/mesenchymal interactions, in which estrogen produced by stromal cells surrounding the tumor acts to stimulate the production of growth factors and cytokines by the tumor cells. Some of these may act to stimulate further the growth and development of the tumor, while these or other factors may act on the surrounding mesenchymal cells in a paracrine fashion to stimulate aromatase expression in the presence of glucocorticoids. Thus, a positive feedback loop is established which leads to the development and growth of the tumor.
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PMID:Expression of transcripts of interleukin-6 and related cytokines by human breast tumors, breast cancer cells, and adipose stromal cells. 873 8

This report describes a companion flow cytometry study (Cancer and Leukemia Group B (CALGB)--8869) using tumors derived from patients enrolled in a large randomized clinical trial (CALGB-8541) performed on 1,572 patients with early stage, node-positive breast cancer. The CALGB initiated an adjuvant breast cancer trial in 1985 to determine if dose intensification (dose of drug per unit time) of chemotherapy was related to relapse-free and overall survival. Patients were randomized by pretreatment clinical variables to one of three different dosage regimens of chemotherapy. Using a tumor enrichment procedure, 442 paraffin-embedded blocks were analyzed by flow cytometry, and S-phase fraction (SPF) was analyzed by three different methods. Ploidy analysis was performed using standard procedures. Tissue from 90% of the patients was suitable for ploidy analysis, whereas only 68% could be assessed for SPF. With a median follow-up time of 80 months, our results show that ploidy status had no clinical utility, whereas high SPF predicted poorer overall survival. The rectangular fit model for SPF was more predictive of outcome than both the area fit model and a computer fit model (modfit) for SPF. In univariate analysis, patients with a low SPF (< 10%) had a better prognosis than those patients with a high SPF (> 10%), but they responded equally well to the different treatment regimens. Patients with high SPF (> 10%) had longer relapse-free and overall survival to high dose chemotherapy compared to low or standard dose chemotherapy. Multivariate analysis indicated that treatment intensity as well as the number of positive nodes, tumor size, steroid receptor status, and c-erb B-2 expression were significant in predicting overall and disease-free survival. The multivariate analysis, however, revealed that SPF was significant in predicting overall but not disease-free survival, but there was no longer any relationship among SPF, dose intensity, and outcome.
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PMID:Flow cytometry in node-positive breast cancer: cancer and leukemia group B protocol 8869. 874 80

Abnormalities of several cell-cycle regulatory genes including cyclin D1, p16CDKN2 and p15CDKN2B have been described in B cell non-Hodgkin's lymphoma (B-NHL). We describe a new B-NHL cell line (Granta 519), with concurrent abnormalities of the cyclin D1, pl6CDKN2 and pl5CDKN2B genes. An independent clinical case of mantle cell NHL (Mc-NHL) with concomitant overexpression of cyclin D1, and deletion of the p16CDKN2 gene was also identified, suggesting that this combination of oncogenic aberration is a pathophysiologic contribution to a subset of NHL cases. More in-depth functional studies of this concept were facilitated by the availability of the cell line Granta 519 which was derived from a case of high-grade NHL and has a mature B cell immunophenotype. Cytogenetic analysis identified translocation t(11;14)(q13;q32) and complex rearrangements involving chromosomes 9p22, 13p21, 17pl1, and 18q21. Molecular analysis identified overexpression of cyclin D1 mRNA and biallelic deletion of the p16CDKN2 and p15CDKN2B genes. To elucidate the effect of these genetic abnormalities on the G1 control of Granta 519 cells, the level and function of the major components of the cyclinD/retinoblastoma (RB) pathway were investigated. Cyclin D1 was dominant among the D-type cyclins, formed abundant complexes with cyclin-dependent kinase (Cdk) Cdk4 rather than Cdk6, and the immunoprecipitated cyclin D1/Cdk4 holoenzyme was active as a pRB kinase. Electroporation of wild-type pl6CDKN2 arrested the Granta 519 cells in G1, consistent with the p16CDKN2 loss as a biologically relevant event during multistep evolution of the tumor, and with the expression of functional pRB. Direct cooperation of these distinct abnormalities to cell-cycle, deregulation in NHL cells was suggested by G1 acceleration upon inducible overexpression of cyclin D1 in a control breast cancer cell line lacking p16CDKN2, an effect which could be prevented by ectopic expression of p16CDKN2. Taken together, these data suggest that concurrent overexpression of cyclin D1 and functional elimination of p16CDKN2 and p15CDKN2B may characterize certain cases of mantle cell NHL, and that cooperation of the abnormalities is likely to provide a growth advantage of the tumour cells through more efficient inactivation of the RB tumor suppressor. Further clinicopathologic studies of this possibility are warranted.
Leukemia 1997 Jan
PMID:Potential role for concurrent abnormalities of the cyclin D1, p16CDKN2 and p15CDKN2B genes in certain B cell non-Hodgkin's lymphomas. Functional studies in a cell line (Granta 519). 900 20

The major cause of treatment failure in hematologic malignancies is the development of resistance to chemotherapeutic agents and the presence of clonogenic tumor cells in remission bone marrow. In the present study, we tested the optimal conditions for activation by interleukin-2 (IL-2) of endogenous bone marrow effector cells to develop cytotoxicity against solid tumor and leukemia cells and the effects of IL-2 treatment on eradication of malignant cells from the marrow product while preserving hematopoiesis. Normal donor bone marrow was contaminated with 10% A549 lung cancer cells, MCF-7 breast cancer, or EM2 leukemia cells, and then combined with peripheral blood-derived lymphokine-activated killer (LAK) cells which had been incubated in the presence of IL-2, 6000 IU/ml, for 5 days. Eradication (A549 and MCF-7) or >90% reduction in tumor cell number (EM2) was achieved upon exposure of the marrow to LAK cells but not to control, non-IL-2-exposed PBMC. The non-cross-resistance of chemotherapy and cell-mediated cytotoxicity were tested by using chemoresistant target cells for LAK cytotoxicity assays. Ara-C-resistant K562 cells were sensitive to LAK cytotoxicity, similar to sensitive controls. Similar effects were seen in daunomycin-resistant HL60 leukemia cells and VP-16-resistant K562 cells. The daunomycin-resistant K562 cells were also sensitive to LAK cell killing similar to sensitive controls. Activation of bone marrow mononuclear cells (BMMC) with IL-2, 6000 IU/ml for 24 h, significantly enhanced cytotoxicity against the NK-resistant, LAK-sensitive Daudi cell line. This procedure did not result in significant loss of total BMMC or hematopoietic colony-forming units. We then studied the possibility that the effector cell activity of the IL-2-activated BMMC which is diminished after removal of the IL-2 at 24 h could be recovered upon re-exposure of the marrow to IL-2. We found that the optimum conditions for preserving cytotoxicity were prolonged continuous exposures to IL-2 but that re-exposure of the 24-h IL-2-activated BMMC to IL-2 after a 1- or 2-week IL-2 withdrawal was associated with full recovery of cytotoxicity. These experiments also demonstrated that the overall recovery of viable cells from the BMMC was over 100%, possibly due to a proliferative effect of the IL-2 exposure on BMMC. These results demonstrate that the use of IL-2-activated marrow in patients with acute leukemia in remission undergoing autologous bone marrow transplantation (aBMT) may overcome the obstacles of clonogenic, drug-resistant minimal residual disease. The effector cell activity and hematopoietic capacity of the activated bone marrow product can also be maintained even if optimal clinical care requires an interruption in the in vivo exposure to IL-2. This therapeutic approach is currently being tested in acute leukemia patients undergoing IL-2-activated aBMT followed by prolonged IL-2 treatment before and after hematologic reconstitution.
Leukemia 1997 May
PMID:Autologous bone marrow purging by in situ IL-2 activation of endogenous killer cells. 918 Feb 98

To study mechanism of chromosomal translocation, we analyzed the breakpoints (b/p) of the PML and RARA genes in 120 and 5 patients with de novo and secondary (therapy-related) acute promyelocytic leukemia (APL), respectively. In de novo APL, the b/p in the PML gene were clustered in introns 3 (bcr 3; 30%) and around intron 6 (bcr 1 and 2: 70%). The b/p of the RARA gene were widely distributed in intron 2. In studied 8 de novo APL patients, no consensus sequence-motif was found around the b/p, but there were identical stretches of one to seven nucleotides between the PML and RARA genes in the joining regions, suggesting non-selective DNA double strand cleavage followed by single strand base-pairing within identical short stretches as a molecular mechanism of the translocation. In 4 secondary APL patients after chemotherapy including etoposide against Langerhans cell histiocytosis, the b/p of the PML gene were located in intron 6, and those of the RARA gene were in a restricted region within intron 2, 1 kb EcoRI-BamHI fragment, while in an APL patient after chemotherapy without etoposide against breast cancer, the b/p of the PML and RARA genes were located in intron 6 and another region within intron 2, respectively. These data suggest that a different mechanism was associated with the t(15;17) translocation in etoposide-related APL.
Leukemia 1997 Apr
PMID:Molecular analysis of the t(15;17) translocation in de novo and secondary acute promyelocytic leukemia. 920 67

HER2 (erbB-2) proto-oncogene amplification and/or overexpression correlate with poor prognosis in many malignancies. The precise biological role of this oncogenic signaling pathway (which also involves the HER4 gene) in breast cancer is unclear. One property conferred by this oncogene relates to response to drug therapy. Clinical studies support an association between HER2 overexpression and resistance to alkylating agents (cisplatinum and cyclophosphamide). Data from the Cancer and Leukemia Group B 8869/8541 study indicate enhanced dose responsiveness to doxorubicin (Adriamycin) in patients who overexpress the HER2 receptor. Heregulin beta-2, a naturally occurring ligand that activates the HER2 receptor by inducing its heterodimerization with the HER4 receptor, has recently been cloned. The ability of this ligand to phosphorylate the HER2 receptor exogenously allows us to study the effect of HER2 activation on cancer cell behavior. To study the relationship between chemotherapy response and activation of HER2, MCF-7 cells expressing biologically active heregulin were assessed for response to doxorubicin and etoposide, both of which are topoisomerase IIalpha (topo IIalpha) inhibitors. Several clones show markedly increased sensitivity to these drugs. In addition, the same wild-type MCF-7 cells transfected with heregulin beta-2 under the control of an inducible promoter also show this dose-response relationship to doxorubicin after the expression of heregulin beta-2 is activated by zinc. The modulation of topo IIalpha was studied in the cell lines transfected with heregulin. topo IIalpha mRNA and protein (total protein and enzymatic decatenating activity) were found to be up-regulated in heregulin beta-2-transfected cells. Moreover, topo IIalpha promoter activity was also modestly increased in heregulin beta-2-transfected cells. Because up-regulation of topo IIalpha in vitro and in clinical specimens is associated with increased response to doxorubicin (presumptively by an increase in drug substrate), this may be the mechanism of the increased sensitivity to doxorubicin seen in heregulin beta-2-transfected cells. This implies that activation of HER2 or one of the other members of the receptor family may increase sensitivity to doxorubicin by up-regulation of topo IIalpha. This finding suggests the use of receptor/ligand expression to direct patient-specific therapeutic choices (e.g., doxorubicin versus alkylator-based regimens) and the use of biological agents (such as heregulin) in combination with certain chemotherapeutic agents to enhance response to treatment in breast cancer patients.
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PMID:Induction of sensitivity to doxorubicin and etoposide by transfection of MCF-7 breast cancer cells with heregulin beta-2. 956 96

Forty of the 550 patients (7%) entered to the 11q23 Workshop had secondary (s) acute lymphoblastic leukemia (nine cases), s-acute myeloid leukemia (25 cases, predominantly of FAB type M5), s-acute leukemia unspecified (one case) or s-myelodysplastic syndrome (five cases) following treatment for a primary malignancy. Breast cancer (12 cases) and non-Hodgkin's lymphoma (eight cases) were the most frequent primaries. Twenty-three patients had been treated with either an epipodophyllotoxin (seven patients) or an anthracycline (10 cases) or both (four cases) frequently combined with alkylating agents (12 cases) and with radiotherapy (six cases). Two further patients had alkylating agents and two had radiotherapy alone. Time between diagnosis of the primary and secondary malignancy was between 10 months and 22 years (median 24 months). The incidence of secondary malignancies in 11q23 subgroups was: t(11;19)(q23;p13.1) (33%), t(9;11) (8%), t(4;11) (5.5%), t(10;11)(5%), t (6;11) (3%), del11q23(2%) and 10 patients had a rare 'other' abnormality. No associations were seen between type of prior malignancy and 11q23 subgroup, or between prior malignancy and leukemia subtype. Remission, when achieved (32 patients), was short (median 5 months). Two patients survived following a bone marrow transplant for s-leukemia and s-myelodysplastic syndrome.
Leukemia 1998 May
PMID:Secondary acute leukemia and myelodysplastic syndrome with 11q23 abnormalities. EU Concerted Action 11q23 Workshop. 959 90

The PTEN/MMAC1 gene at 10q23.3, which has dual specific phosphatase activity, is a novel tumor suppressor gene candidate. Various kinds of tumors have mutations in this gene, including glioblastoma, endometrial carcinoma and prostate cancer. We examined 29 cases of primary non-Hodgkin's lymphoma (NHL) for mutations in the PTEN/MMAC1 gene. One case of diffuse large B cell lymphoma had an 11 bp deletion, but the remaining 28 cases showed no mutations in the genome. Two of these 28 cases showed missense mutations in the PTEN/MMAC1 transcripts, but no alterations in the genomic DNA. These mRNA missense variants are similar to PTEN/MMAC1 transcript aberrations which have been reported in patients with breast cancer. These findings suggest that alterations in the PTEN/MMAC1 gene play a role in the pathogenesis of NHL.
Leukemia 1998 Aug
PMID:Mutational analysis of the PTEN/MMAC1 gene in non-Hodgkin's lymphoma. 969 84

Amonafide is a new imide derivative of naphthalic acid. The drug had demonstrated significant activity in preclinical studies and some activity in Phase I trials. The drug is extensively metabolized and detected in plasma and urine. Its toxicity has previously been correlated to the formation of an active metabolite, N-acetyl-amonafide. Amonafide was chosen for inclusion in the Cancer and Leukemia Group B (CALGB) master metastatic breast cancer protocol. CALGB 8642 randomizes previously untreated metastatic breast cancer patients either to one of several Phase II agents given for up to four cycles and then followed by standard cyclophosphamide-doxorubicin-5-fluorouracil, or to immediate treatment with standard cyclophosphamide-doxorubicin-5-fluorouracil. The end point of CALGB 8642 is to assess the difference in survival, toxicity, and overall response when limited exposure to Phase II agents precedes standard chemotherapy. This report deals only with amonafide as a Phase II agent. Comparisons with the cyclophosphamide-doxorubicin-5-fluorouracil arm will not be addressed. Patients had to have histologically documented measurable breast cancer and a performance status of 0-1. Patients could not have had prior chemotherapy for metastatic disease. Prior adjuvant chemotherapy was permitted. Patients could not have visceral crisis. Amonafide was given at 300 mg/m2/day i.v. for 5 days, and repeated at 21-day intervals for a maximum of four cycles. Escalation and reduction in dose was mandated dependent on hematotoxicity or lack thereof. Toxicity was primarily hematological and bimodal: 32% had grade 3 or 4 leukopenia and 24% had grade 3 or 4 thrombocytopenia; 22% had no leukopenia and 44% had no thrombocytopenia. The response rate was 18%, including one complete response. When response was analyzed by hematological toxicity, there was a 35.7% response if patients had leukopenia grade 3/4 (versus 8.3%, P = 0.08). There was a 50% response if patients had thrombocytopenia grade 3/4 (versus 7.1%, P = <0.01). We conclude that amonafide is somewhat active in previously untreated breast cancer patients. There may be a steep dose-response curve, based on the significant correlation between myelosuppression and response. Rates of responses in patients adequately dosed (i.e., with significant hematotoxicity) with amonafide ranged from 35 to 50%. Further studies will incorporate individualized dosing based on pretreatment acetylator phenotyping.
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PMID:Amonafide: An active agent in the treatment of previously untreated advanced breast cancer--a cancer and leukemia group B study (CALGB 8642). 981 35


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