Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Neither retinoic acid receptor-beta (RARbeta) nor insulin-like growth factor-binding protein-3 (IGFBP-3) is expressed in breast cancer cell line MCF-7. The expression of both proteins can be induced in response to all-trans-retinoic acid (atRA). By using an RARalpha-selective antagonist (Ro 41-5253), we demonstrated that RARbeta expression was induced by atRA through an RARalpha-dependent signaling pathway and that RARbeta induction was correlated with IGFBP-3 induction. However, MCF-7 cells transfected with sense RARbeta cDNA expressed IGFBP-3 even in the presence of the RARalpha-selective antagonist Ro 41-5253. On the other hand, antisense RARbeta cDNA transfection of MCF-7 cells blocked atRA-induced IGFBP-3 expression, indicating that RARbeta is directly involved in the mediation of IGFBP-3 induction by atRA. Induction of IGFBP-3 expression by atRA occurs at the transcriptional level, as measured by nuclear run-on assays. Finally, we showed that atRA-induced IGFBP-3 is functionally active in modulating the growth-promoting effect of IGF-I. These experiments indicate that RARalpha and RARbeta, both individually and together, are important in mammary gland homeostasis and breast cancer development. By linking IGFBP-3 to RARbeta, our experiments define the signal intersection between the retinoid and IGF systems in cell growth regulation and explain why loss of RARbeta might be critical in breast cancer carcinogenesis/progression.
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PMID:Signal relay by retinoic acid receptors alpha and beta in the retinoic acid-induced expression of insulin-like growth factor-binding protein-3 in breast cancer cells. 1036 50

The formation of oestrone sulphate has been examined in MCF-7 (oestrogen receptor positive, ER+) and MDA-MB-231 (ER negative, ER-) breast cancer cells. Using intact cell monolayers and a physiological substrate concentration, progesterone (1 microM) and dexamethasone (1 microM) both increased oestrone sulphate formation in MCF-7 cells. In MDA-MB-231 cells, dexamethasone, but not progesterone, increased conjugate formation. A number of growth factors, cytokines and human serum albumin (HSA), which have previously been found to regulate oestrogen synthesis, were also examined for their ability to regulate oestrone sulphate formation. In MCF-7 cells epidermal growth factor, acidic and basic fibroblast growth factors, insulin-like growth factor-type I and insulin all stimulated oestrone sulphate formation. The cytokines, tumour necrosis factor alpha (TNFalpha) and interleukin-1beta also increased conjugate formation in the ER+ cells, as did HSA. In contrast, in MDA-MB-231 cells TNFalpha was without effect and HSA inhibited oestrone sulphate formation. The ability to modulate oestrone sulphate formation in ER+ cells may be an important mechanism to limit the availability of oestrogen to interact with the ER.
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PMID:The regulation of oestrone sulphate formation in breast cancer cells. 1036 10

The Wilms' tumor suppressor gene (WT1), a nuclear transcription factor, regulates the expression of the insulin-like growth factor (IGF) and transforming growth factor (TGF) systems, both of which are implicated in breast tumorigenesis. WT1 allelic integrity was examined by loss of heterozygosity (LOH) studies in formalin-fixed, paraffin-embedded (FFPE) ductal carcinoma in situ (DCIS, n = 20) and fresh frozen primary invasive breast carcinomas (n = 24). Loss of heterozygosity (LOH) at the WT1 locus (11p13) was examined by PCR evaluation of an Hinf1 restriction fragment length polymorphism (RFLP) and correlated to tumor stage (in situ and invasive). After identification of the heterozygous/informative breast lesions, 1 of 12 (8.3%) DCIS (high-grade micropapillary) and 3 of 14 (21.4%) of infiltrating carcinomas (high grade) showed loss of one allele, suggesting that LOH of the WT1 locus is a rare genetic event in early breast cancer, becoming more common in invasive and in high-grade lesions.
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PMID:Loss of heterozygosity of the Wilms' tumor suppressor gene (WT1) in in situ and invasive breast carcinoma. 1037 74

We investigated the secretion of insulin-like growth factor binding proteins (IGFBPs) by estrogen-dependent ZR-75-1 and MCF-7 human breast cancer cells, and tamoxifen-resistant (ZR-75-9a1 and LY2) and estrogen-independent (ZR-PR-LT) variants which express altered levels of IGF-I receptor. IGFBP species (35 kDa and 44 kDa) were detectable in conditioned serum-free medium (SFM) by immunoblotting and positively identified as IGFBP-2 and -3, respectively. Secretion of IGFBP-2 into SFM by the tamoxifen-resistant and estrogen-independent cell lines was markedly reduced and secretion into SFM of the 24-kDa species, assigned the identity of IGFBP-4, was also reduced in the tamoxifen-resistant lines. There was no clear correlation between patterns of IGFBP secretion and IGF-I receptor expression.
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PMID:Changes in the secretion of insulin-like growth factor binding proteins -2 and -4 associated with the development of tamoxifen resistance and estrogen independence in human breast cancer cell lines. 1039 68

The last decade has been characterized by a major investigative thrust into the physiology of two unique but ubiquitous peptides, insulin-like growth factor (IGF)-I and IGF-II. The regulatory systems that control the tissue bioactivity of the IGFs have been delineated, and subcellular signaling mechanisms have been clarified. Clearly, both tissue and circulating growth factor concentrations are important in defining the relationship between IGF-I and cell activity. Bone, liver, and circulatory IGF-I have received the most attention by investigators, in part because of the ease of measurement and the interaction with disease states such as osteoporosis. More recently, attention has focused on the role IGF-I plays in neoplastic transformation and growth. Two large prospective observational studies have demonstrated greater risk for prostate and breast cancer associated with high circulating concentrations of IGF-I. Animal models and in vitro studies confirm that there is a close, albeit complex, interaction between IGF-I signaling and bone turnover. This report will focus on: (a) IGF physiology, including IGF ligands, binding proteins, and proteases; (b) the relationship between IGF-I and bone mass in respect to risk for osteoporosis; (c) the heritable regulation of the IGF-I phenotype; and (d) the association between serum IGF-I and cancer risk. The IGFs remain a major area for basic and clinical investigations; future studies may define both diagnostic and therapeutic roles for these peptides or their related proteins in several disease states.
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PMID:Serum insulin-like growth factors and insulin-like growth factor-binding proteins: clinical implications. 1043 Aug 22

Endothelial differentiation gene-encoded G protein-coupled receptors (Edg Rs) Edg-1, Edg-3, and Edg-5 bind sphingosine 1-phosphate (S1P), and Edg-2 and Edg-4 Rs bind lysophosphatidic acid (LPA). LPA and S1P initiate ras- and rho-dependent signaling of cellular growth. Cultured lines of human breast cancer cells (BCCs) express Edg-3 > Edg-4 > Edg-5 > or = Edg-2, without detectable Edg-1, by both assessment of mRNA and Western blots with rabbit and monoclonal mouse anti-Edg R antibodies. BCC proliferation was stimulated significantly by 10(-9) M to 10(-6) M LPA and S1P. Luciferase constructs containing the serum response element (SRE) of growth-related gene promoters reported mean activation of BCCs by LPA and S1P of up to 85-fold. LPA and S1P stimulated BCC secretion of type II insulin-like growth factor (IGF-II) by 2-7-fold, to levels at which exogenous IGF-II stimulated increased proliferation and SRE activation of BCCs. All BCC responses to LPA and S1P were suppressed similarly by pertussis toxin, mitogen-activated protein kinase kinase inhibitors, and C3 exoenzyme inactivation of rho, suggesting mediation by Edg Rs. Monoclonal anti-IGF-II and anti-IGFR1 antibodies suppressed proliferation and SRE reports of BCCs to LPA and S1P by means of up to 65%. Edg Rs thus transduce LPA and S1P enhancement of BCC growth, both directly through SRE and indirectly by enhancing the contribution of IGF-II.
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PMID:Dual mechanisms for lysophospholipid induction of proliferation of human breast carcinoma cells. 1049 33

Earlier studies in our laboratory demonstrated that the steroidal antiestrogen ICI 182,780 is very effective in abolishing the tamoxifen-resistant proliferation of MCF 7/5-23 cells. In addition, preliminary binding studies showed that ICI 182,780 increased the binding of insulin-like growth factor (IGF)-I to the MCF 7/5-23 cells, although this finding was not the result of an increase in the expression of the insulin-like growth factor-I receptor (IGF-IR). Hence, we reasoned that the inhibition of tamoxifen-resistant cell growth by ICI 182,780 might have been due to increased expression of insulin-like growth factor binding proteins (IGFBPs). We observed the up-regulation of non-insulin-suppressible IGF-I binding in both the tamoxifen-sensitive MCF 7/5-21 cell line (1.5-fold) and the tamoxifen-resistant MCF 7/5-23 cell line (2.5-fold) after 5 days of treatment with ICI 182,780 (10(-7) M) in serum-free medium, suggesting a role for cell-associated IGFBPs. Affinity cross-linking experiments confirmed the presence of an IGF-I:IGFBP complex of approximately 38-kDa in tamoxifen or ICI 182,780-treated cells. Western ligand blots showed higher levels of a soluble 30-kDa IGFBP in media conditioned by either of the subclones that had been treated with ICI 182,780, an effect consistently opposed by estrogen (E2: 10(-9) M). RT-PCR showed higher levels of IGFBP-5 mRNA than any of the other known IGFBPs, suggesting that this was the major IGFBP subtype. The protein was subsequently identified by Western immunoblotting as IGFBP-5. In conclusion, we postulate that this may be a mechanism contributing to the greater potency of ICI 182,780 in the growth inhibition of the MCF 7/5-23, tamoxifen-resistant cell line.
Breast Cancer Res Treat 1999 Jun
PMID:Induction of insulin-like growth factor binding protein expression by ICI 182,780 in a tamoxifen-resistant human breast cancer cell line. 1051 68

This study was designed to evaluate time and dose dependency of alterations in insulin-like growth factor (IGF)-I, free IGF-I and the functional status of IGF-binding protein (IGFBP)-3 in breast cancer patients during treatment with megestrol acetate (MA). In 16 patients receiving MA 160 mg daily, total IGF-I levels increased gradually (significant after 3 days on treatment) by a maximum of 2.66-fold after 5-6 months on treatment. However, free (readily dissociable) IGF-I levels increased to a smaller extent (1.23-2.15-fold). This discrepancy may be due to an increase in intact IGFBP-3 determined by Western ligand blotting (WLB). Similar findings were observed in 12 patients treated with MA in escalating doses from 40-800 mg daily. A dose-dependent increase in IGF-I was observed up to a dose level of 120 mg daily. We conclude that treatment with MA caused a profound increase in plasma levels of total IGF-I accompanied by a moderate increase in free IGF-I. This may explain the anabolic effects of MA in patients suffering from cachexia, but refute the hypothesis that alterations in the IGF-system may contribute to the antitumour effects of MA in breast cancer patients.
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PMID:Effects of treatment with megestrol acetate on the insulin-like growth factor system: time and dose dependency. 1053 50

Breast cancer is associated with endogenous hormone levels, but the exact relation and underlying mechanisms remain unclear. Data from several recent epidemiologic studies suggest that a woman who experiences preeclampsia in her own pregnancy, or who was herself born to a preeclamptic pregnancy, is at reduced risk for breast cancer later in life. This paper reviews the evidence for a connection between preeclampsia and breast cancer risk, and discusses the hormonal mechanisms that might explain this association. Preeclampsia is characterized by reduced levels of estrogens and insulin-like growth factor-1, and by elevated levels of progesterone, androgens, human chorionic gonadotropin, IGF-1 binding protein, corticotropin-releasing factor, cortisol, and insulin. These factors may act both individually and synergistically to decrease breast cancer risk. The occurrence of preeclampsia during a woman's pregnancy may reflect an underlying hormonal profile that both predisposes her to preeclampsia and reduces her risk for breast cancer. In addition, the major hormonal alterations associated with preeclampsia during gestation may have lasting effects on subsequent breast cancer risk. Finally, the hormonal and nutritional environment of the womb, for which preeclampsia is a marker, may play an important role in programming lifelong risk for breast cancer in the female offspring.
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PMID:Preeclampsia and breast cancer risk. 1053 87

We have demonstrated previously that insulin-like growth factor binding protein (IGFBP)-3 alone has little growth inhibitory effect on Hs578T human breast cancer cells, but that it can dramatically accentuate the apoptotic response to the physiological trigger, ceramide, in an IGF-independent manner. We have now studied the potential of other IGFBPs (1-6) to interact with apoptotic signalling pathways. Hs578T cells were preincubated with a binding protein (100 ng/ml) for 24 h, followed by co-incubation of the binding protein with an apoptotic dose of ceramide or RGD-containing peptide for a further 24 h. Apoptosis was assessed using flow cytometry, MTT (3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; thiazolyl blue) assay and morphological assessment. Binding protein profiles were determined using ligand and immunoblotting techniques. Each of the IGFBPs (1-6) alone had no significant (P > 0. 05) growth inhibitory effects relative to control cells. In contrast to IGFBP-3, which significantly (P < 0.05) accentuated C2-induced apoptosis, IGFBP-1, -2, and -6 had no effect, whereas IGFBP-4 and -5 each caused marked (P < 0.01) inhibition of ceramide-induced programmed cell death. Apoptosis induced by RGD was also significantly (P < 0.05) reduced by IGFBP-5, whereas IGFBP-3 had no effect. These data provide evidence to suggest that individual IGFBPs have specific IGF-independent effects and act differentially on apoptotic signalling pathways.
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PMID:Differential IGF-independent effects of insulin-like growth factor binding proteins (1-6) on apoptosis of breast epithelial cells. 1057 48


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