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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The insulin-like growth factor (IGF) family of ligands, receptors, and binding proteins can regulate breast cancer cell proliferation in vitro, and interruption of these pathways inhibits IGF-mediated cell proliferation. If the IGF family members are key regulators of breast cancer growth and progression in vivo, we would expect their expression to be an indicator of the prognosis of the disease. Thus, measurement of IGF expression may provide an indicator of the growth effect within a tumor, and provide new targets for treatment of the disease. In this review we will summarize the data generated thus far indicating that IGF family members are indicators of prognosis of breast cancer, and that measurement of the whole IGF family in concert may provide useful information for treatment strategies of breast cancer.
Breast Cancer Res Treat 1998 Feb
PMID:IGF system components as prognostic markers in breast cancer. 951 83

Potential antiproliferative effects of tocotrienols, the major vitamin E component in palm oil, were investigated on the growth of both estrogen-responsive (ER+) MCF7 human breast cancer cells and estrogen-unresponsive (ER-) MDA-MB-231 human breast cancer cells, and effects were compared with those of alpha-tocopherol (alphaT). The tocotrienol-rich fraction (TRF) of palm oil inhibited growth of MCF7 cells in both the presence and absence of estradiol with a nonlinear dose-response but such that complete suppression of growth was achieved at 8 microg/mL. MDA-MB-231 cells were also inhibited by TRF but with a linear dose-response such that 20 microg/mL TRF was needed for complete growth suppression. Separation of the TRF into individual tocotrienols revealed that all fractions could inhibit growth of both ER+ and ER- cells and of ER+ cells in both the presence and absence of estradiol. However, the gamma- and delta-fractions were the most inhibitory. Complete inhibition of MCF7 cell growth was achieved at 6 microg/mL of gamma-tocotrienol/delta-tocotrienol (gammaT3/deltaT3) in the absence of estradiol and 10 microg/mL of deltaT3 in the presence of estradiol, whereas complete suppression of MDA-MB-231 cell growth was not achieved even at concentrations of 10 microg/mL of deltaT3. By contrast to these inhibitory effects of tocotrienols, alphaT had no inhibitory effect on MCF7 cell growth in either the presence or the absence of estradiol, nor on MDA-MB-231 cell growth. These results confirm studies using other sublines of human breast cancer cells and demonstrate that tocotrienols can exert direct inhibitory effects on the growth of breast cancer cells. In searching for the mechanism of inhibition, studies of the effects of TRF on estrogen-regulated pS2 gene expression in MCF7 cells showed that tocotrienols do not act via an estrogen receptor-mediated pathway and must therefore act differently from estrogen antagonists. Furthermore, tocotrienols did not increase levels of growth-inhibitory insulin-like growth factor binding proteins (IGFBP) in MCF7 cells, implying also a different mechanism from that proposed for retinoic acid inhibition of estrogen-responsive breast cancer cell growth. Inhibition of the growth of breast cancer cells by tocotrienols could have important clinical implications not only because tocotrienols are able to inhibit the growth of both ER+ and ER- phenotypes but also because ER+ cells could be growth-inhibited in the presence as well as in the absence of estradiol. Future clinical applications of TRF could come from potential growth suppression of ER+ breast cancer cells otherwise resistant to growth inhibition by antiestrogens and retinoic acid.
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PMID:Tocotrienols inhibit the growth of human breast cancer cells irrespective of estrogen receptor status. 962 93

To define genes that are essential to the initiation and progression of breast cancer we utilized subtractive hybridization and differential display cloning techniques and isolated over 950 cDNAs from breast cell-lines derived from matched normal and tumor tissue. Of these, 102 cDNAs were characterized by DNA sequencing and Northern blot analysis. GenBank searches showed that one of these genes, T1A12 is identical to mac25, an insulin-like growth factor-binding protein related gene. Antibodies generated against the C-terminal region of the T1A12/mac25 protein were used to investigate its expression in 60 primary breast tissues. Sections of 12 benign, 16 ductal carcinoma in situ and 32 infiltrating ductal carcinoma specimens were examined. Strong immunoperoxidase staining was observed in luminal epithelial cells of normal lobules and ducts, in apocrine cells of cysts and fibroadenomas. Moderate to weak protein expression was found in hyperplastic and DCIS cells, but no specific staining was detected in invasive carcinoma cells. FISH mapping using a PAC clone localized the T1A12/mac25 gene to 4q12-13. Microsatellite length polymorphism was studied using markers for 4q in paired normal and tumor breast tissues. Thirty-three per cent (10/30) of the samples were found to be polymorphic with D4S189 and D4S231 microsatellite markers and LOH was detected in 50% (5/10) of these informative samples. Our data indicate that T1A12/mac25 expression is abrogated during breast cancer progression concomitant with loss of heterozygosity on chromosome 4q. T1A12/mac25 may therefore have a tumor suppressor-like function and its expression could indicate a disease with a more favorable status, having a better prognosis.
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PMID:Down-regulation of T1A12/mac25, a novel insulin-like growth factor binding protein related gene, is associated with disease progression in breast carcinomas. 962 12

Connective Tissue Growth Factor (CTGF) is a cysteine-rich peptide involved in human atherosclerosis and fibrotic disorders such as scleroderma. CTGF has considerable N-terminal sequence similarity with the insulin-like growth factor binding proteins (IGFBPs), including preservation of cysteines, and has been postulated to be a member of the IGFBP superfamily. Indeed, recent studies have shown that baculovirus generated CTGF, a secreted 38-kDa protein, binds IGFs in a specific manner, leading to the provisional renaming of CTGF as IGFBP-8 (or IGFBP-rP2). With immunoprecipitation and immunoblotting, using polyclonal anti-IGFBP-rP2 antibody generated against recombinant human IGFBP-rP2bac, IGFBP-rP2 can be identified in the serum-free conditioned media of Hs578T human breast cancer cells, as well as in various human biological fluids, such as normal sera, pregnancy sera, and cerebrospinal, amniotic, follicular and peritoneal fluids. Glycosylation studies with endoglycosidase F reveal that endogenous human IGFBP-rP2 is a secreted, glycosylated, approximately 32-38-kDa protein with 2-8-kDa of N-linked sugars and a 30-kDa core. There are 18- and 24-kDa proteins that appear to be IGFBP-rP2 degradation products. In Hs578T human breast cancer cells, transforming growth factor (TGF)-beta 2, a potent growth inhibitor for these cells, upregulates IGFBP-rP2 mRNA and protein levels. Expression of Hs578T IGFBP-rP2 is significantly increased by TGF-beta 2 treatment in a dose-dependent manner, with 2.5- and 6-fold increases in mRNA and protein levels, respectively, at a TGF-beta 2 concentration of 10 ng/ml. Our studies indicate that IGFBP-rP2 appears to be an important endocrine factor, and one of the critical downstream effectors of the critical downstream effectors of TGF-beta, similar to the role of IGFBP-3 in TGF-beta-induced growth inhibition in human breast cancer cells.
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PMID:Identification of glycosylated 38-kDa connective tissue growth factor (IGFBP-related protein 2) and proteolytic fragments in human biological fluids, and up-regulation of IGFBP-rP2 expression by TGF-beta in Hs578T human breast cancer cells. 966 51

The highly tumorigenic human breast cancer MCF-7ras line (Ha-ras-transfected MCF-7 cell line) loses estrogen dependence and secretes diffusible growth factors that support its own tumor growth in vivo. Our previous studies showed that carboxymethyl benzylamide dextran (CMDB7) inhibits the growth of breast MCF-7 and MCF-7ras cell lines. In this study, we have shown that conditioned medium (CM) from MCF-7 and MCF-7ras cells stimulated the DNA synthesis of BALB/c3T3 fibroblasts and that CMDB7 strongly inhibited these mitogenic effects in a dose-dependent manner. Neutralizing antibodies against platelet-derived growth factor (PDGF) partially inhibited the mitogenic effect of MCF-7ras CM. The flow cytometry analysis of the cell cycle showed that the CM of tumor cells increased the percentage of fibroblasts in S phase and that CMDB7 blocked them in G0/G1 phase. CMDB7 inhibited the mitogenic effect of PDGF-BB and transforming growth factor (TGF) beta1 but not those of epidermal growth factors and insulin-like growth factor on BALB/c3T3 fibroblasts. CMDB7 increased the electrophoretic mobility of radiolabeled PDGF-BB and TGF-beta1, apparently by forming a stable complex with these factors. On intact BALB/c3T3 fibroblasts, binding of iodinated growth factors (125I-TGF-beta1 and 125I-PDGF) to their receptors was completely displaced by CMDB7. In vivo studies demonstrated that s.c. injection of CMDB7 inhibited by 66% the tumor growth of MCF-7ras xenografts in nude mice. These results showed that CMDB7 inhibits the mitogenic effect of growth factors released from MCF-7 and MCF-7ras cells and suppresses tumor growth in the MCF-7ras model.
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PMID:Inhibition of MCF-7ras tumor growth by carboxymethyl benzylamide dextran: blockage of the paracrine effect and receptor binding of transforming growth factor beta1 and platelet-derived growth factor-BB. 966 68

Examination of estrogen-responsive processes in cell culture is used to investigate hormonal influence on cancer cell growth and gene expression. Most experimental studies have used breast cancer cell lines, in particular MCF7 cells, to investigate estrogen responsiveness. In this study we examined an ovarian cancer cell line, BG-1, which is highly estrogen-responsive in vitro. This observation, plus the fact that the cells are of ovarian rather than mammary gland origin, makes it an attractive alternative model. 17Beta-estradiol, epidermal growth factor, and insulin-like growth factorinduced proliferation of BG-1 and MCF7 cells. Viability was dependent on these growth factors in BG-1 cells, but not in MCF7 cells. Therefore, we examined the differences between these two cell lines with respect to estrogen and growth factor receptors. BG-1 cells have twice as many estrogen receptors as MCF7 cells, and BG-1 cells have higher insulin-like growth factor-1 and epidermal growth factor receptor levels than MCF7 cells. This may also explain why BG-1 cells proliferate 56% more robustly in serum and show more serum dependence in culture. In both BG-1 and MCF7 cells, epidermal growth factor receptor number is low (<20000/cell), while insulin-like growth factor-1 receptor level was highest in estrogen receptor positive cell lines. For example, insulin-like growth factor-1 receptor was higher in BG-1 and MCF7 cells than in estrogen receptor negative cells (HeLa > MDA-MB-435 > HBL100). In conclusion, BG-1 cells are an excellent model for understanding hormone responsiveness in ovarian tissue and an alternative for examining estrogen receptor-mediated and insulin-like growth factor-1/epidermal growth factor/estrogen cross-talk processes because of their sensitivity to these factors.
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PMID:BG-1 ovarian cell line: an alternative model for examining estrogen-dependent growth in vitro. 976 51

Suramin represents a new class of antitumor drugs that targets growth factor networks. In this Phase II trial, suramin was administered by continuous infusion to 10 patients with advanced breast cancer. The target level of 280 microgram/ml suramin was achieved in a median of 10 days; toxicities in this patient group were low. We monitored the insulin-like growth factor (IGF) network in these patients because of the previously defined growth-promoting role of the IGFs in breast cancer. Plasma levels of total IGF-I and total IGF-II showed variable responses to suramin with median decreases of 24 and 23%, respectively, for the 10 patients; for total IGF-I levels, this did not reach statistical significance. On the other hand, free IGF-I plasma levels were consistently and dramatically increased (over 250%) after suramin infusion. IGF-binding proteins (IGFBPs), modulators of IGF bioavailability, were also measured. Levels of IGFBP-3, the major carrier of IGFs in the circulation, were decreased 21% after suramin treatment when measured by immunoradiometric assay. However, the majority of the plasma IGFBP-3 remaining after suramin was not the intact high-affinity IGF-binding form but rather a 30-kDa fragment with markedly reduced affinity for IGF-I. IGFBP-3 protease activity was evident in the plasma of 3 of 10 patients after suramin. Measurements of plasma IGFBP-1, IGFBP-2, and IGFBP-4 revealed no significant changes in response to suramin. The dramatic increase in active free IGF-I seen after suramin raises concern and underscores the importance of measuring relevant biomarkers in clinical trials.
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PMID:Evaluation of continuous infusion suramin in metastatic breast cancer: impact on plasma levels of insulin-like growth factors (IGFs) and IGF-binding proteins. 981 55

The pure antiestrogen ICI 182,780 inhibits insulin-like growth factor (IGF)-dependent proliferation in hormone-responsive breast cancer cells. However, the interactions of ICI 182,780 with IGF-I receptor (IGF-IR) intracellular signaling have not been characterized. Here, we studied the effects of ICI 182,780 on IGF-IR signal transduction in MCF-7 breast cancer cells and in MCF-7-derived clones overexpressing either the IGF-IR or its 2 major substrates, insulin receptor substrate 1 (IRS-1) or src/collagen homology proteins (SHC). ICI 182,780 blocked the basal and IGF-I-induced growth in all studied cells in a dose-dependent manner; however, the clones with the greatest IRS-1 overexpression were clearly least sensitive to the drug. Pursuing ICI 182,780 interaction with IRS-1, we found that the antiestrogen reduced IRS-1 expression and tyrosine phosphorylation in several cell lines in the presence or absence of IGF-I. Moreover, in IRS-1-overexpressing cells, ICI 182,780 decreased IRS-1/p85 and IRS-1/GRB2 binding. The effects of ICI 182,780 on IGF-IR protein expression were not significant; however, the drug suppressed IGF-I-induced (but not basal) IGF-IR tyrosine phosphorylation. The expression and tyrosine phosphorylation of SHC as well as SHC/GRB binding were not influenced by ICI 182,780. In summary, downregulation of IRS-1 may represent one of the mechanisms by which ICI 182,780 inhibits the growth of breast cancer cells. Thus, overexpression of IRS-1 in breast tumors could contribute to the development of antiestrogen resistance.
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PMID:Insulin receptor substrate 1 is a target for the pure antiestrogen ICI 182,780 in breast cancer cells. 1018 34

Interaction of epithelial cells with the extracellular matrix is mediated through integrin receptors, which transmit signals regulating cell growth, differentiation and death. Occupation of these receptors, via Arg-Gly-Asp (RGD) recognition sequences, leads to activation of focal adhesion kinase (FAK). We treated human breast cancer cell lines with RGD-containing peptides, which can disrupt integrin attachment, and investigated alterations in FAK phosphorylation, cell detachment and death. Cells grown in vitro were treated with insulin-like growth factor-binding protein-1 (IGFBP-1) and a small, synthetic RGD-containing peptide (Gly-Arg-Gly-Asp-Thr-Pro) and its negative control peptide RGE (Arg-Gly-Glu-Ser) for either 30 min followed by immunoprecipitation of cell lysates with anti-phosphotyrosine and Western immunoblotting with anti-FAK or for 24 h followed by cell counting, immunocytochemistry and flow cytometry. Both IGFBP-1 (0-800 ng/ml) and the synthetic RGD-containing peptide (1-100 microg/ml) caused significant dephosphorylation of FAK. Furthermore, after 24 h both peptides caused detachment from the matrix and the induction of apoptosis. We conclude from these data that IGFBP-1 can interact with integrin receptors to induce FAK dephosphorylation and subsequently influence attachment and cell death.
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PMID:Effect of insulin-like growth factor binding protein-1 on integrin signalling and the induction of apoptosis in human breast cancer cells. 1019 17

Cross-talk between insulin-like growth factor (IGF)- and estrogen receptor (ER)-signaling pathways results in synergistic growth. We show here that estrogen enhances IGF signaling by inducing expression of three key IGF-regulatory molecules, the type 1 IGF receptor (IGFR1) and its downstream signaling molecules, insulin receptor substrate (IRS)-1 and IRS-2. Estrogen induction of IGFR1 and IRS expression resulted in enhanced tyrosine phosphorylation of IRS-1 after IGF-I stimulation, followed by enhanced mitogen-activated protein kinase activation. To examine whether these pathways were similarly activated in vivo, we examined MCF-7 cells grown as xenografts in athymic mice. IRS-1 was expressed at high levels in estrogen-dependent growth of MCF-7 xenografts, but withdrawal of estrogen, which decreased tumor growth, resulted in a dramatic decrease in IRS-1 expression. Finally, we have shown that high IRS-1 expression is an indicator of early disease recurrence in ER-positive human primary breast tumors. Taken together, these data not only reinforce the concept of cross-talk between IGF- and ER-signaling pathways, but indicate that IGF molecules may be critical regulators of estrogen-mediated growth and breast cancer pathogenesis.
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PMID:Enhancement of insulin-like growth factor signaling in human breast cancer: estrogen regulation of insulin receptor substrate-1 expression in vitro and in vivo. 1031 28


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