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

Although the amplified in breast cancer 1 (AIB1) coactivator is amplified and overexpressed in breast cancers, its role in mammary carcinogenesis remains unknown. We demonstrate that during mammary development and tumorigenesis, the elevation of AIB1 level and its nuclear localization correlate with normal and transformed mammary epithelial proliferation, whereas its lower expression and cytoplasmic localization correlate with mammary epithelial quiescence and differentiation. In this study, the role of AIB1 in breast tumor initiation, progression, and metastasis was studied by generating AIB1(+/+), AIB1(+/-), and AIB1(-/-) mice harboring the mouse mammary tumor virus/v-Ha-ras (ras) transgene that induces breast tumors. Breast tumor incidence was reduced dramatically in the intact AIB1(-/-)-ras virgin mice and inhibited completely in the ovariectomized AIB1(-/-)-ras mice. Breast tumor latency was delayed significantly in AIB1(-/-)-ras virgin mice with natural estrous cycles, multiparous mice with cyclically elevated reproductive hormones, and virgin mice bearing pituitary isografts with persistently elevated hormones. Although AIB1 deficiency significantly suppressed mammary tumorigenesis under all of the concentrations of ovarian hormones, it did not affect the promotional role of ovarian hormones on mammary tumorigenesis, suggesting that AIB1 and ovarian hormones contribute to mammary carcinogenesis through different pathways. AIB1 deficiency did not alter the expression of estrogen and progesterone-responsive genes in the mammary gland, but it caused partial resistance to the insulin-like growth factor I because of a significant reduction in the insulin receptor substrates. The impaired insulin-like growth factor I pathway in AIB1(-/-)-ras mammary epithelium and tumor cells was responsible in part for the suppression of mammary tumorigenesis and metastasis caused by inhibition of cell proliferation and migration. These results suggest that a more effective strategy to control breast cancer is to target AIB1-mediated and ovarian hormone-initiated pathways.
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PMID:AIB1/SRC-3 deficiency affects insulin-like growth factor I signaling pathway and suppresses v-Ha-ras-induced breast cancer initiation and progression in mice. 1499 52

The insulin-like growth factors, particularly IGF-II, interact with multiple cell surface receptors. One of these receptors, the insulin-like growth factor II/mannose 6-phosphate receptor (IGF2R, also called the Type II IGF receptor), has a structure distinct from IGF1R or the insulin receptor. While IGF2R binds IGF-II with high affinity, it also serves as a cell surface receptor for many other proteins relevant to breast cancer biology. As such, IGF2R could play a role in several different key cellular functions including IGF-II action, lysosome biogenesis, and regulation of several novel ligands. These possibilities, along with the intriguing demonstration of loss of heterozygosity at the IGF2R locus, provide clues that this receptor could have an important function in breast cancer. This review will discuss potential ways that IGF2R could influence breast cancer biology.
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PMID:The insulin-like growth factor II/mannose 6-phosphate receptor: implications for IGF action in breast cancer. 1568 78

IRS-1 (Insulin Receptor Substrate-1) is an adaptor protein important for insulin and IGF-I receptor (Insulin-like Growth Factor-IR) transduction to downstream targets. One mechanism recently identified to downregulate IGF-I or insulin receptor signaling in diabetic models is IRS-1 Ser(312) phosphorylation. To date, the importance of this residue in cancer is unknown. This paper identifies mechanisms leading to Ser(312) regulation in MCF-7 breast cancer cells. Whereas IGF-I phosphorylation of IRS(312) is PI (phosphatidylinositol) 3-kinase dependent, anisomycin stress treatment requires JNK activation to induce phosphorylation of IRS(312). We show that both IGF-I and anisomycin stress treatment converge downstream onto mTOR (Mammalian Target of Rapamycin) and PKCdelta (Protein Kinase C-delta) to induce IRS-1 Ser(312) phosphorylation. mTOR associates with IRS-1 and is primarily required for Ser(312) phosphorylation in response to stress or IGF-I treatment. PKCdelta binds to mTOR and its activity is also important for stress or IGF-I mediated Ser(312) phosphorylation. Thus, mTOR and PKCdelta convey diverse signals to regulate IRS-1 function.
Breast Cancer Res Treat 2005 Jun
PMID:PKCdelta and mTOR interact to regulate stress and IGF-I induced IRS-1 Ser312 phosphorylation in breast cancer cells. 1595 59

The IGFs are ubiquitous and have pleoitropic effects. They are critical for normal growth and development, and for normal functioning of adult tissues. A liver-specific gene-deletion knockout of the IGF-I gene resulted in a mouse model with reduced circulating IGF-I levels, that led to insulin resistance due to the secondary elevation of circulating GH levels. The reduction in circulating IGF-I levels was also associated with a reduction in cancer growth and metastases in three cancer models, one for colon cancer and two for breast cancer. A second mouse model, using the transgenic approach, inhibited the IGF-I and insulin receptor function in skeletal muscle, and resulted in severe insulin resistance in muscle followed by insulin resistance in fat and liver and, eventually, beta-cell dysfunction and development of Type 2 diabetes. This progression from insulin resistance to Type 2 diabetes was most likely due to lipotoxicity with elevated serum and tissue triglyceride levels. Evidence supporting the hypothesis came from the use of fibrates and leptin injections, each of which enhanced fatty acid (FA) oxidation in liver and muscle and was associated with a reversal of the insulin resistance and diabetes.
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PMID:Studies involving the GH-IGF axis: Lessons from IGF-I and IGF-I receptor gene targeting mouse models. 1611 70

The phosphatidylinositol 3-kinase (PI3-K) signalling pathway has been implicated in breast cancer development and resistance to therapy. Akt-1 and serum and glucocorticoid-induced kinase-1 (SGK-1) are homologous kinases which are important downstream effectors of PI3-K signalling. We sought to determine the individual expression patterns of these two kinases in order to better understand their respective roles in PI3-K signalling in breast cancer. To this end, we examined the expression of both p-Akt-1 and SGK-1 in 40 breast cancers. p-Akt-1 expression was seen in 58% of tumour samples, while SGK-1 overexpression was detected in 48%. Interestingly, a highly significant association was found between the expression of p-Akt-1 and SGK-1 (P=0.002), suggesting complementary physiological functions in PI3-K signalling. This finding is consistent with recent genetic data from Caenorhabditis elegans suggesting that both SGK-1 and Akt-1 are required for signalling downstream of insulin receptor activation.
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PMID:Coordinate expression of the PI3-kinase downstream effectors serum and glucocorticoid-induced kinase (SGK-1) and Akt-1 in human breast cancer. 1624 46

The insulin-like growth factor (IGF) system plays an important role in a variety of physiologic processes and in diseases such as cancer. Although the role of the IGF system in cancer has been recognized many years ago, components of the system have only recently been targeted and shown to affect cell transformation, proliferation, survival, motility, and migration in tissue cultures and in mouse models of cancer. We have been hypothesizing that targeting IGF-II in addition to blocking its interaction with the IGF receptor type I (IGF-IR) would also allow to block that portion of the signal transduction through the insulin receptor that is due to its interaction with IGF-II. Lowering its level may also not induce up-regulation of its production as for IGF-I. Finally, targeting a diffusable ligand as IGF-II may not require penetration of the antibody inside tumors but could shift the equilibrium to IGF-II complexed with antibody so the ligand concentration would decrease in the tumor environment without the need for the antibody to penetrate the tumor. Here, we describe the identification and characterization of three novel anti-IGF-II fully human monoclonal antibodies. They bound with high (subnanomolar) affinity to IGF-II, did not cross-react with IGF-I and insulin, and potently inhibited signal transduction mediated by the IGF-IR interaction with IGF-II. The most potent neutralizer, IgG1 m610, inhibited phosphorylation of the IGF-IR and the insulin receptor, as well as phosphorylation of the downstream kinases Akt and mitogen-activated protein kinase with an IC(50) of the order of 1 nmol/L at IGF-II concentration of 10 nmol/L. It also inhibited growth of the prostate cancer cell line DU145 and migration of the breast cancer line cells MCF-7. These results indicate an immunotherapeutic potential of IgG1 m610 likely in combination with other antibodies and anticancer drugs but only further experiments in mouse models of cancer and human clinical trials could evaluate this possibility.
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PMID:Novel human monoclonal antibodies to insulin-like growth factor (IGF)-II that potently inhibit the IGF receptor type I signal transduction function. 1643 69

Insulin-like growth factor-I (IGF-I), IGF-II, and insulin have all been implicated in regulating several aspects of the malignant phenotype via the type I IGF receptor (IGF1R) and insulin receptor (IR). We have previously shown that a chimeric single-chain antibody against IGF1R (scFv-Fc) and a murine antibody EM164 down-regulate IGF1R, making breast cancer cells unresponsive to IGF-I. To determine if IR signaling is affected, we examined regulation of IR in MCF-7 cells after exposure to these antibodies. Surprisingly, both scFv-Fc and EM164 resulted in decreased levels of IR in vitro and in vivo despite their lack of reactivity against IR. Twenty-four-hour pretreatment with EM164 also inhibited insulin-mediated phosphorylation of IR and insulin-stimulated proliferation of MCF-7 cells. Neither scFv-Fc nor EM164 caused down-regulation of IR in cells that express very low levels of IGF1R or no IGF1R. Expression of IGF1R was required for IR down-regulation, which was specific as neither antibody caused down-regulation of beta1 integrin or epidermal growth factor receptor. Reagents that disrupt lipid rafts inhibited IR down-regulation by the antibodies, suggesting that IR in close physical proximity to IGF1R in lipid rafts was being endocytosed. Our data show that down-regulation of IR by monoclonal antibodies against IGF1R requires the coexpression of IGF1R and may be due to endocytosis of hybrid IR/IGF1R or holo-IR. Thus, antibodies against IGF1R provide inhibition of both IGF and insulin signaling in cancer cells.
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PMID:Down-regulation of insulin receptor by antibodies against the type I insulin-like growth factor receptor: implications for anti-insulin-like growth factor therapy in breast cancer. 1648 46

Various studies have shown that the insulin receptor (IR) is increased in most human breast cancers, and both ligand-dependent malignant transformation and increased cell growth occur in cultured breast cells overexpressing the IR. However, although numerous in vivo and in vitro observations have indicated an important contributory role for the IR in breast cancer cell biology, the molecular mechanisms accounting for increased IR expression in breast tumors have not previously been elucidated. Herein, we did immunoblot analyses of nuclear protein from cultured breast cancer cells and normal and tumoral tissues from breast cancer patients combined with promoter studies by using a series of human wild-type and mutant IR promoter constructs. We provide evidence that IR overexpression in breast cancer is dependent on the assembly of a transcriptionally active multiprotein-DNA complex, which includes the high-mobility group A1 (HMGA1) protein, the developmentally regulated activator protein-2 (AP-2) transcription factor and the ubiquitously expressed transcription factor Sp1. In cultured breast cancer cells and human breast cancer specimens, the expression of AP-2 was significantly higher than that observed in cells and tissues derived from normal breast, and this overexpression paralleled the increase in IR expression. However, AP-2 DNA-binding activity was undetectable with the IR gene promoter, suggesting that transactivation of this gene by AP-2 might occur indirectly through physical and functional cooperation with HMGA1 and Sp1. Our findings support this hypothesis and suggest that in affected individuals, hyperactivation of the AP-2 gene through the overexpression of IR may play a key role in breast carcinogenesis.
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PMID:Activator protein-2 overexpression accounts for increased insulin receptor expression in human breast cancer. 1670 31

The signaling cascades activated by insulin and IGF-1 contribute to the control of multiple cellular functions, including glucose metabolism and cell proliferation. In most cases these effects are mediated, at least in part, by insulin receptor substrates (IRS), one of which is insulin receptor substrate 1 (IRS-1). R-Ras is a member of the Ras family of GTPases and is involved in a variety of biological processes, including integrin activation, cell migration, and control of cell proliferation. Here we demonstrate that both R-Ras and BCAR3, a regulator of R-Ras activity that has been implicated in breast cancer, regulate the level of IRS-1 protein in estrogen-dependent MCF-7 and ZR75 breast cancer cells. In particular, expression of a constitutively activated R-Ras mutant, R-Ras38V, or of BCAR3 accelerates the degradation of IRS-1, leading to the impairment of signaling through insulin but not epidermal growth factor receptors. Moreover, knockdown of endogenous R-Ras levels in MCF-7 cells inhibits IRS-1 degradation induced by estrogen signaling blockade but not by long-term insulin treatment. Consistent with these results, both R-Ras38V expression and estrogen signaling blockade lead to the degradation of IRS-1, at least in part, through calpain activity. These findings show that R-Ras activity mediates inhibition of insulin signaling associated with suppression of estrogen action, implicating this GTPase in a growth-inhibitory mechanism associated with antiestrogen treatment of breast cancer.
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PMID:The R-Ras GTPase mediates cross talk between estrogen and insulin signaling in breast cancer cells. 1691 23

Visfatin was originally identified as a growth factor for immature B cells, and recently demonstrated to bind insulin receptor. Visfatin mRNA and protein were detected by RT-PCR and Western blot analysis in cloned bovine mammary epithelial cells, lactating bovine mammary gland and human breast cancer cell line, MCF-7. Immunocytochemical staining localized the visfatin protein in the cytosol and nucleus of both cells. Quantitative-RT-PCR analysis revealed that the expression of the visfatin mRNA was significantly elevated when treated with forskolin (500 microM), isopreterenol (1-10 microM) and dibutyric cyclic AMP (1 mM) for 24 h, and significantly reduced when treated with insulin (5-50 ng/ml) and dexsamethasone (0.5-250 nM) for 24 h. These results indicate that mammary epithelial cells express the visfatin protein and secrete them into the milk.
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PMID:Visfatin is present in bovine mammary epithelial cells, lactating mammary gland and milk, and its expression is regulated by cAMP pathway. 1712 17


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