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)

Human breast cancer cells (HBCC) secrete at least four different forms of IGFBPs. We have previously demonstrated that hIGFBP-1 is a minor component of IGFBPs secreted by Hs578T cells and is absent in CM from MCF-7 cells. In our present report, we describe the immunological and structural relationship of HBCC IGFBPs to hIGFBP-2 and hIGFBP-3. Analysis of conditioned media (CM) from Hs578T by Western ligand blotting revealed three IGFBPs of apparent Mr = 38K, 28K, and 24K; CM from MCF-7 revealed only two IGFBPs, of apparent Mr = 31K and 24K. Immunoprecipitation studies with polyclonal antibodies raised against hIGFBP-2 and hIGFBP-3 demonstrated that the 38K IGFBP in Hs578T CM is immunologically related to hIGFBP-3, while the 31K IGFBP in MCF-7 cells is related to the hIGFBP-2. Analysis by Northern blot demonstrated that MCF-7 cells contained mRNA for hIGFBP-2, while Hs578T cells contained the mRNA characteristic of the hIGFBP-3. The identity of the 24K IGFBP remains unknown, and may represent a distinct IGFBP. Of note, assay of CM following removal of BPs by acid chromatography demonstrated no detectable IGF-I or -II. The role of these IGFBPs in HBCC is of interest in view of the potential modulation of IGF actions by these proteins.
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PMID:Insulin-like growth factor binding proteins in human breast cancer cells: relationship to hIGFBP-2 and hIGFBP-3. 169 78

P19 EPI-7, a differentiated murine embryonal carcinoma cell line with an epithelioid morphology, does not require external growth factors for proliferation under clonal and subconfluent conditions. At saturation density, however, cells become quiescent in the G1/G0 phase of the cell cycle from which they can be restimulated, particularly upon addition of epidermal growth factor. Medium conditioned by confluent P19 EPI-7 cultures is able to enhance clonal outgrowth of this cell line, suggesting that autocrine growth factor loops may be acting in these cells. Analysis of conditioned serum-free medium shows that this cell line produces a platelet-derived growth factor-like growth factor, next to a type beta transforming growth factor and large amounts of insulin-like growth factor II (IGF-II) and an IGF-binding protein with high specificity for IGF-II. This latter observation has been confirmed by the use of a specific bioassay for IGFs, based on their ability to specifically stimulate proliferation of MCF-7 human breast cancer cells. The amount of IGF-II produced (0.5 mg/liter conditioned medium) makes P19 EPI-7 one of the best producing cell lines for this factor described so far. Receptor cross-linking analysis shows that this cell line contains IGF-I receptors, but no specific receptors for IGF-II. Depending on the conditions tested, transforming growth factor-beta 1 either act as a growth-stimulating factor or as a strong growth inhibitory factor. These data demonstrate that upon cellular differentiation, embryonal carcinoma cells can be formed which produce polypeptide growth factors and are also able to respond to such factors. These observations are discussed in the light of the role of autocrine and paracrine growth stimulation processes during early murine development.
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PMID:Production of insulin-like growth factors, platelet-derived growth factor, and transforming growth factors and their role in the density-dependent growth regulation of a differentiated embryonal carcinoma cell line. 253 20

The pathogenesis and progression of breast cancer involve complex interactions between hormones and polypeptide growth factors such as insulin-like growth factor-I (IGF-I). IGF-I has been found in stromal fibroblasts derived from malignant and benign breast tissue and it is a mitogen for several breast cancer cell lines. It circulates bound to specific high-affinity binding proteins, which could act as either positive or negative modulators of tumorigenesis. This study has been addressed to characterize IGF-I and its binding proteins in the serum of 85 unselected patients with early breast cancer. The IGF-I concentration was assessed by radioimmunoassay of 69 out of 85 samples before and after dissociation of the IGF-I and IGF-binding protein (IGF-BP) complex whereas IGF-BP of all 85 sera were analyzed by Western ligand blotting; estradiol and progesterone were measured by radioimmunoassay in native serum samples. In our study no differences in IGF-I serum levels between pre- and post-menopausal patients were observed. Patients with higher estradiol and progesterone serum levels did not present different IGF-I concentrations compared to patients with lower serum levels. Furthermore, IGF-I median values were not found to depend on estrogen receptor (ER) status. A heterogeneous quali-quantitative molecular pattern of binding proteins was detected: IGF-BP3 and IGF-BP1 were the most and the least expressed respectively. No correlations between ER status, or parameters related to the hormonal status, and IGF-I or binding proteins expression were observed. No significant differences in IGF-I concentration and IGF-BP expression were observed between cancer patients and a control group matched for age and menopausal status. Finally, preliminary collection of 20 sera derived from patients with late breast cancer was analyzed for IGF-I and its binding proteins content.
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PMID:Insulin-like growth factor-I (IGF-I) and IGF-binding proteins blood serum levels in women with early- and late-stage breast cancer: mutual relationship and possible correlations with patients' hormonal status. 759 32

Neutralization of insulin-like growth factor action by insulin-like growth factor binding protein-1 inhibits the in vitro growth of breast cancer cells. We performed this study to determine the pharmacokinetic profile of recombinant human IGFBP-1 (rhIGFBP-1) in athymic mice as a prelude to testing this protein in a human tumor xenograft model. After the subcutaneous injection of 1 mg, rhIGFBP-1 migrating at 29 kDa could be detected by ligand blotting and immunoblotting. Plasma concentrations of rhIGFBP-1 were quantified by immunoassay and demonstrated a half-life was 2.49 hours with the maximal concentration of 43.5 micrograms/mL occurring at 1 hour. The area under the concentration-time curve was 78.32 micrograms x hr/mL. Plasma clearance was 12.77 mL/hr and the mean residence time was 1.96 hours. rhIGFBP-1 was also detected in some tissues and was also cleared rapidly. These results show that high plasma and tissue levels of rhIGFBP-1 can be obtained after subcutaneous injection in athymic mice, however, the short half-life of the protein may limit its therapeutic use.
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PMID:Pharmacokinetic profile of recombination human insulin-like growth factor binding protein-1 in athymic mice. 888 72

Estrogen and IGF-I are potent mitogens for most breast cancer cell lines, and although their signaling pathways contrast, there is considerable interaction between them. Recent evidence indicating that IGF-I can alter estrogen receptor (ER) action led us to investigate whether an inhibitor of IGF-I action. IGF-binding protein-1 (IGFBP-1), could affect transcriptional activation of ER. First, we confirmed that tamoxifen (TAM) could inhibit IGF-I-mediated proliferation of MCF-7 cells. Although TAM can increase IGFBP-3 expression in MCF-7 cells, and this binding protein has been shown to be able to inhibit IGF action, TAM had no effect on IGF-I-stimulated tyrosine phosphorylation of IGF-I receptor or the downstream signaling molecule, insulin receptor substrate-1. Therefore, to confirm that IGF-I was affecting transcriptional activation of ER, we utilized a gene reporter assay using a single consensus estrogen response element (ERE-tk-luc) upstream of luciferase. As expected, estradiol (E2; 1nM) increased transcriptional activation three- to fivefold from the ERE in three ER-positive breast cancer cell lines (MCF-7, ZR-75 and T47D). A 2.5-to 4-fold increase was also seen with IGF-I (5 nM). TAM (1 microM) effectively blocked activation by E2 and IGF-I, indicating disruption of ER-mediated transcription. As expected, human recombinant IGFBP-1 (80 nM) completely inhibited IGF-I-mediated activation of ER, however, IGFBP-1 also caused a significant decrease in E2-mediated activation. We also noticed that IGF-I increased the activity of all plasmids that we cotransfected including TATA-luc, SV40-luc and pGL Basic. This effect was post-transcriptional, as it was not affected by actinomycin D (2 micrograms/ml), while we were able to completely inhibit E2-mediated transcriptional activation of ERE-tk-luc. Unlike the complete inhibition of ER-mediated transcriptional activation by actinomycin D, IGF-I-mediated transactivation was reduced by only 50%, indicating that the activation by IGF-I represented both transcriptional and post-transcriptional effects. This study confirmed that IGF-I can cause transcriptional activation of endogenous ER in human breast cancel cells, and inhibition of ER action by IGFBP-1 suggests that IGF-1 signaling may be necessary for maximal ER activation.
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PMID:Activation of estrogen receptor-mediated gene transcription by IGF-I in human breast cancer cells. 901 38

Insulin-like growth factor (IGF)-I is one of the most potent mitogens to many breast cancer cell lines in vitro. Effective growth inhibition in vitro may be achieved by antibodies to the type I IGF receptor (IGF-IR) or by using antisense strategies. Most human breast cancers express IGF-IR in vivo. Thus, different therapeutic strategies aimed at inhibiting ligand stimulation of the IGF-IR may be an attractive treatment option against breast cancer. Several drugs commonly used in breast cancer influence the IGF system both in vitro and in vivo. While antioestrogens such as tamoxifen and droloxifene reduce the expression of IGF-IR in vitro and suppress plasma levels of IGF-I but elevate IGF-binding protein-1 in vivo, megestrol acetate may reduce the delivery of IGFs to the tissues by inhibition of IGFBP-3 protease activity.
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PMID:Insulin-like growth factors in breast cancer. 914 60

Insulin-like growth factor (IGF) -independent growth inhibition of human breast cancer cells, Hs578T, by IGF-binding protein-3 (IGFBP-3) has previously been demonstrated. Cell growth is a balance between proliferation and programmed cell death (apoptosis). We have investigated whether IGFBP-3 can affect apoptosis of Hs578T cells. As no induction of apoptosis was found, we also investigated its effect on the response to ceramide, an intracellular second messenger that mediates the signal for apoptosis. Using the cell permeable ceramide analogue, C2, induction of apoptosis was established by 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide) assay, trypan blue uptake, morphological criteria, and flow cytometry. Incubation of cells with non-glycosylated IGFBP-3 (ngIGFBP-3; 0.5-100 ng/ml) resulted in no growth inhibition or increase in apoptosis; whereas, C2 (1-30 microM) resulted in a dose-dependent induction of apoptosis. Addition of IGFs to the cells, alone or with C2, elicited no response in terms of proliferation or survival, respectively. When the cells were preincubated with ngIGFBP-3 before addition of C2 (2-5 microM), apoptosis was accentuated in a dose-dependent manner (at 100 ng/ml IGFBP-3, apoptosis increased from 11 to 88%). In conclusion, we found that IGFBP-3 had no direct inhibitory effect on Hs578T cells but could accentuate apoptosis induced by the physiological trigger ceramide in an IGF-independent manner.
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PMID:Insulin-like growth factor-binding protein (IGFBP-3) predisposes breast cancer cells to programmed cell death in a non-IGF-dependent manner. 932 80

Serum insulin-like growth factor (IGF)-I and IGF-binding protein-3 levels were measured in two groups of postmenopausal women with advanced breast cancer, who received the aromatase inhibitor letrozole 0.5 or 2.5 mg p.o. once daily. Blood samples were obtained from 15 patients in each dose group at baseline, and one and three months after starting therapy. Circulating IGF-I and IGFBP-3 concentrations were determined by means of radioimmunoassay. In both dosage groups a statistically significant increase in the IGF-I levels was observed during three months of letrozole treatment (P=0.003). In addition, the multiple testing procedure yielded in the whole patient population a significant result in the comparison between mean IGF-I values after three months of therapy and those observed at baseline (P=0.004), the estimated average increase being of 24%. No significant result was obtained in the analysis for the dose effect (P=0.077) and for the time x dose interaction (P=0.208). Circulating IGFBP-3 levels did not appear to be affected by letrozole treatment in either of the dose groups. This is the first report concerning the short-term effects of letrozole on components of the IGF system in breast cancer patients; further investigations are warranted in order to confirm these preliminary data.
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PMID:The aromatase inhibitor letrozole in advanced breast cancer: effects on serum insulin-like growth factor (IGF)-I and IGF-binding protein-3 levels. 945 92

Leptin reflects the amount of energy stores, regulates energy balance and is associated with circulating levels of reproductive hormones and insulin-like growth factor-I (IGF-I). Breast cancer has also been associated with obesity, reproductive hormones and circulating IGF-I levels. To determine whether leptin is involved in the etiology of breast cancer, we compared serum leptin levels in 83 cases of pre-menopausal carcinoma in situ of the breast and 69 healthy controls recruited in Massachusetts. Serum leptin levels were 13.69 + 1.3 ng/ml in cases and 16.03 + 1.7 ng/ml in controls. Data were also analyzed using multiple logistic regression with adjustment for known risk factors for the development of breast cancer as well as anthropometric, demographic and hormonal variables, including estradiol, prolactin, IGF-I and IGF-binding protein-3. Odds ratios were 1.75 (95% CI, 0.73-4.21) for the second control-defined tertile and 1.54 (0.46-5.16) for the third control-defined tertile relative to the first. Thus, leptin does not appear to increase the risk of pre-menopausal breast cancer in situ substantially.
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PMID:Leptin in relation to carcinoma in situ of the breast: a study of pre-menopausal cases and controls. 993 51

Insulin-like growth factors (IGFs) in the circulation are predominantly sequestered into ternary complexes comprising IGF, IGF-binding protein-3 (IGFBP-3), and the acid-labile subunit (ALS). Besides its role in regulating IGF bioavailability in the circulation, IGFBP-3 has both IGF-dependent and IGF-independent actions on cell proliferation. As part of our studies into the structure-function relationships of the multifunctional IGFBP-3, we have evaluated the efficiency of an adenovirus-mediated expression system for rapid, medium-scale production of functional, glycosylated IGFBP-3. Replication-deficient adenovirus containing human IGFBP-3 cDNA was generated using standard techniques. Secreted, recombinant IGFBP-3 (IGFBP-3(Ad)) was purified from the culture medium of virus-infected cells by IGF-I affinity chromatography followed by reverse-phase HPLC. When analyzed by SDS-PAGE, IGFBP-3(Ad) was similar in size (43- to 45-kDa glycoform doublet) to IGFBP-3(Pl) derived from plasma. In addition, IGFBP-3(Ad) was detected by immunoblot using an antibody specific for human IGFBP-3 and by ligand blot using radiolabeled IGF-I. IGFBP-3(Ad) had similar affinities for IGF-I and ALS and an approximately 25% decreased affinity for IGF-II compared to IGFBP-3(Pl). IGFBP-3(Ad) showed no significant difference in its susceptibility to an IGFBP-3 protease present in medium conditioned by MCF-7 breast cancer cells compared to IGFBP-3(Pl), but appeared more resistant to the IGFBP-3 protease present in pregnancy serum. IGFBP-3(Ad) also exhibited increased binding to T47D cells which may be related to the glycosylation state of the protein.
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PMID:Adenoviral-mediated expression of human insulin-like growth factor-binding protein-3. 1033 78


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