Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278488 (metastatic breast cancer)
 7,812 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The influence of the novel antiprogestin onapristone on the serum insulin-like growth factor (IGF) system was studied in a group of 13 postmenopausal women with metastatic breast cancer. Blood samples were obtained before treatment and subsequently after 1, 2 and 3 months on therapy. IGF-I, IGF-II and IGF-binding protein (IGFBP)-2 were measured by radioimmunoassay (RIA). In addition, the IGFBP profile was evaluated by Western ligand blotting (WLB), and IGFBP-3 fragmentation determined by immunoblotting. A moderate (29%) but significant increase in IGF-I was observed after 3 months on treatment (p < 0.05). IGFBP-2 showed a significant, progressive increase during treatment when evaluated both by WLB (44% increase over baseline at 3 months) and by RIA (33% increase over baseline at 3 months). There was a non-significant trend towards an initial decrease in IGFBP-3 fragmentation. No significant alterations were observed in IGF-II or any of the binding proteins (except IGFBP-2) determined by Western ligand blotting. Due to the observation that onapristone treatment caused a moderate suppression of serum cortisol and androstenedione, we postulate the observed increase in IGF-I to be due to a slight glucocorticoid agonistic effect of the drug. On the contrary, the increase in IGFBP-2 may be related to disease progression as has been observed in patients suffering from prostatic cancer.
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PMID:Influence of treatment with onapristone on the IGF-system in breast cancer patients. 971 50

The type I insulin-like growth factor receptor (IGF-IR) plays an important role in the growth and transformation of breast cancer cells. In this study, we investigated the effects of treatment with an antisense IGF-IR construct on cells from the highly metastatic estrogen receptor-negative human breast cancer cell line MDA-MB-435s. The cells carrying the antisense IGF-IR had a markedly reduced expression of IGF-IR, had a significant decrease in cell proliferation, and lost the ability to form colonies in soft agar. There was a delay in tumor formation and a dramatic reduction in tumor size when cells carrying the antisense IGF-IR were injected into either nude or severe combined immunodeficient (scid) beige mice. We have also provided data that show that the scid beige mouse is a more suitable model for studying metastasis of the MDA-MB-435s cells. All of the scid beige mice injected with cells carrying the control construct had metastasis to the lungs, whereas lungs from the nude mice had no apparent metastatic sites after 11 weeks. When cells carrying antisense IGF-IR were injected subcutaneously in scid beige mice, the animals had a significant increase in survival compared with mice injected with cells carrying the control construct. Taken together, these results indicate that the IGF-IR can play a critical role in the progression of breast cancer. Our studies provide a basis for the development of future treatment strategies targeting the IGF-IR in metastatic breast cancer.
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PMID:Treatment of human breast cancer cells with antisense RNA to the type I insulin-like growth factor receptor inhibits cell growth, suppresses tumorigenesis, alters the metastatic potential, and prolongs survival in vivo. 1076 44

Increased expression and activation of receptor tyrosine kinases occurs frequently in human breast carcinomas. Several therapies targeting these receptors are currently in clinical trials. Therapeutic strategies include blockade of individual receptors with monoclonal antibodies and inhibition of tyrosine kinase function. Trastuzumab is the first of these biologic therapies to be approved for patients with human epidermal growth factor receptor 2 (HER2)-overexpressing metastatic breast cancer. Novel trastuzumab-based combinations are being investigated in patients with advanced breast cancer. Large clinical trials have also been launched in the adjuvant setting. Small molecules that inhibit specific tyrosine kinases (e.g., epidermal growth factor receptor, HER2) are in phase I and phase II clinical trials. Other growth-factor-targeted drugs that have reached clinical development include STI571 and antibodies directed at the insulin-like growth factor pathway. Biologic therapies directed against these important receptors are promising. In this review we discuss challenges and opportunities for the development of growth-factor-targeted approaches for the treatment of breast cancer.
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PMID:Growth factor receptors in breast cancer: potential for therapeutic intervention. 1260 28

The aim of this randomised study was to compare the effects of progestins and aromatase inactivators on bone remodelling markers and the components of insulin-like growth factor in patients with metastatic breast cancer. Within the framework of a large (769 patients), randomised double-blind clinical trial comparing exemestane (EXE) with megestrol acetate (MA), serum 17 beta-estradiol (E2), estrone (E1), estrone sulphate (E1S), bone alkaline phosphatase (BAP), carboxy-terminal cross-linking telopeptide of type I collagen (ICTP) and the components of insulin-like growth factor (IGF) family (IGF-1, IGF-2 and IGFBP-3) were determined in 53 patients (24 randomised to EXE and 29 ramdomised to MA). After eight weeks of treatment, both ICTP and BAP increased (p < 0.01) in the EXE group, but only ICTP in the MA group (p < 0.03). The 8-week suppression of E2 and E1S was more pronounced in the EXE group (to, respectively, 11.2% and 9.9% of baseline values) than in the MA group (33.1% and 29.7%). IGF-1 increased (p < 0.01) in both groups, but more so in the patients treated with MA. Estrogen levels negatively correlated with ICTP in both groups, but were not related to BAP in either. IGF-1 negatively correlated with estrogens in both groups. The results of this study indicate that anti-aromatase therapy is associated with increased osteoclast activity, and suggest the existence of possible differential effects of different hormonal therapies on bone remodelling markers regardless of the estrogen suppression induced by EXE.
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PMID:Bone turnover markers and insulin-like growth factor components in metastatic breast cancer: results from a randomised trial of exemestane vs megestrol acetate. 1292 95

A variety of molecules including growth factors are involved in the metastasis of breast cancer cells to bone. We have investigated the effects of osteoblast derived growth factors, such as insulin-like growth factor-1 (IGF-1) and transforming growth factor beta-1 (TGF-beta1), on doxorubicin (adriamycin)-induced apoptosis and growth arrest of estrogen receptor positive (ER+) (MCF-7) and negative (ER-) (MDA-MB-435) breast cancer cell lines. Human breast normal epithelial (MCF-10A), breast cancer (MCF-7) and metastatic breast cancer (MDA-MB-435) cell lines were exposed to different doses of doxorubicin (0.1, 1 or 10 microM) at various exposure times (12, 24 or 48 h). The doxorubicin cytotoxicity was found to be higher in cancer cell lines (MDA-MB-435 and MCF-7) compared with normal breast epithelial cells (MCF-10A cells). Doxorubicin appeared to exert a blockade of MCF-7 and MDA-MB-435 cells at the G2/M phase, and induced apoptosis in MDA-MB-435 (29 +/- 4.2% vs 3.4 +/- 1.9% control) as assessed by flow cytometry, DNA fragmentation and terminal deoxynucleotidyl-transferase mediated deoxyuridine 5-triphosphate and biotin nick-end labelling (TUNEL) assays. Estradiol (E2) stimulated the growth of MCF-7 cells and increased the distribution of the cells at the G2/M and S phases. Exogenous IGF-1 partially neutralized the doxorubicin cytotoxicity in both cancer cell lines (MCF-7 and MDA-MB-435). Similarly, TGF-beta1 partially neutralized the doxorubicin cytotoxicity in MDA-MB-435 cells by reducing the number of cells at the <G1 phase (from 29% to 6.4%) and enhanced the doxorubicin blockade of MCF-7 (E2-) at the G0/G1 phase. Results showed that the osteoblast-derived growth factors could affect the chemotherapy response of breast cancer cells, thereby allowing for the possibility of chemotherapeutic modulation.
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PMID:Growth factors and chemotherapeutic modulation of breast cancer cells. 1295 4

Despite improvements in therapy, the prognosis for advanced breast cancer is poor and a search for new treatment targets and key regulators of tumour growth is warranted. Extensive data are available on the importance of the insulin-like growth factor (IGF) system in growth regulation of breast cancer cell lines in vitro, indicating that the IGF-I receptor (IGF-IR), IGF-I (and IGF-II) function as survival factors, while IGF binding protein (IGFBP)-3 may act as a growth inhibitor. There is a tight link between the growth regulatory pathways of IGFs and oestrogens in oestrogen-receptor(OR)-positive breast cancer cells. In vivo studies indicate a role of IGF-I and IGF-IR in breast cancer development. However, the importance of the IGF system in metastatic and highly aggressive breast tumours in vivo is not clear, and therapeutic strategies designed to interrupt IGF signalling have not yet proved to be an effective treatment modality in patients with metastatic breast cancer.
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PMID:The insulin-like growth factor system in advanced breast cancer. 1468 98

While there have been significant improvements in breast cancer therapy over the last few decades, the fact that metastatic breast cancer remains incurable as well as the finding that adjuvant therapy reduces the breast cancer death hazard ratio by about 30% only underlines the need for novel therapeutic strategies. Currently, there is much interest in 'targeting therapy' for different malignancies. The majority of breast cancers harbour the insulin-like growth factor (IGF)-1 receptor, and IGF-1 has been found to be one of the most potent mitogens to breast cancer cells in vitro. Recent findings that the level of IGF-1 predicts subsequent risk of breast cancer in premenopausal patients further underlines the potential biological importance of this growth factor to the disease. While endocrine treatment with anti-oestrogens as well as progestins have been found to interact with the IGF system in vivo, the extent of these effects on antitumour action remains poorly understood. This paper discusses current strategies and results aiming at targeting IGF-1 as therapy for breast cancer.
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PMID:IGF-1 and breast cancer. 1556 31

The insulin-like growth factor (IGF) system plays an important role in breast tumorigenesis. Breast cancer cells express the type I IGF receptor (IGF-IR) and respond to IGFs in the environment. Tissue-type plasminogen activator (tPA) has been shown to be associated with neoplastic transformation and the invasive phenotype for highly aggressive tumors; however, its role in breast cancer remains unclear. We asked whether there is a relationship between the IGF system and tPA in estrogen receptor-negative breast cancer cells that could contribute to invasion. When MDA-MB-435s breast cancer cells were exposed to IGF-I, tPA messenger RNA (mRNA) was upregulated in a time-dependent fashion. Tissue-type plasminogen activator protein accumulation was also increased in a similar manner. The invasiveness of MDA-MB-435s cells was enhanced in the presence of IGF-I. When the MDA-MB-435s cells were stably transfected with an antisense IGF-IR expression construct, the transfectants expressed high levels of IGF-IR antisense, dramatically reduced levels of endogenous IGF-IR, and a decrease in relative staining intensity for IGF-IR protein. A marked suppression in tPA mRNA expression occurred in MDA-MB-435s cells accompanying inhibition of IGF-IR. When cells carrying the antisense IGF-IR expression construct were exposed to IGF-I, tPA protein accumulation was significantly lower than that of control transfected cells. To our knowledge, this study is the first to show a relationship between the IGF system and tPA. Strategies that target the IGF/tPA pathway could provide alternative treatments for patients with certain types of metastatic breast cancer.
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PMID:Tissue-type plasminogen activator is upregulated in metastatic breast cancer cells exposed to insulin-like growth factor-I. 1627 85

Clinical studies indicate that Herceptin (trastuzumab), a recombinant humanized monoclonal antibody directed against the human epidermal growth factor receptor-2 (HER-2) tyrosine kinase growth factor receptor, provides a significant but transient survival advantage to a subset of patients with HER-2-overexpressing metastatic breast cancer when given as a first-line agent. Increased insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling has recently been identified as a potential factor adversely influencing the response to Herceptin. We examined the effect of recombinant human IGF binding protein 3 (rhIGFBP-3), an antagonist of IGF-IR signaling, in Herceptin-resistant breast cells in vitro and in tumors in vivo. Consistent with results obtained using HER-2- or IGF-IR-transfected cells (MCF-7/HER2-18 and SKBR3/IGF-IR, respectively), we found that rhIGFBP-3 significantly reduced IGF-I-induced IGF-IR phosphorylation and displayed a synergistic interaction with Herceptin against cultured HER-2-overexpressing breast cancer cells in vitro. We show, for the first time, the antitumor activity of rhIGFBP-3 against advanced-stage MCF-7/HER2-18-transfected human breast cancer xenografts and its potentiation of Herceptin activity. We also provide evidence that IGF-IR activation counters the early suppressive effect of Herceptin on HER-2 signaling via Akt and p44/p42 mitogen-activated protein kinase (MAPK), and that inhibition of HER-2-overexpressing human breast tumor growth by rhIGFBP-3 is associated with restored down-regulation of Akt and p44/p42 MAPK phosphorylation in vitro and in vivo. These results emphasize the merit of evaluating simultaneous blockade of the HER-2 and IGF-IR pathways using combination therapy with rhIGFBP-3 plus Herceptin in human clinical trials of patients with HER-2-positive breast cancer.
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PMID:Recombinant human insulin-like growth factor binding protein 3 inhibits growth of human epidermal growth factor receptor-2-overexpressing breast tumors and potentiates herceptin activity in vivo. 1684 73

A patient previously treated for bilateral breast cancer with mastectomy, radiation therapy and in remission on hormonal therapy for more than five years presented with abdominal symptoms from breast cancer relapse. She developed inappropriate polyuria and hypernatraemia, which responded to desmopressin. In combination with the absence of a high signal from the posterior lobe of the pituitary on MRI , these data indicated the presence of partial central diabetes insipidus. The anterior pituitary showed partial failure (low follicle-stimulating hormone, luteinising hormone and insulin-like growth factor-1 levels). Furthermore, primary adrenal insufficiency had developed, ascribed to bilateral tumour invasion of the adrenals. This rare combination of endocrinological failures in a patient with metastatic breast cancer is discussed.
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PMID:Diabetes insipidus and adrenal insufficiency in a patient with metastatic breast cancer. 1699 Jun 96


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