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Search Results: 1 - 10 of 170336 matches for " Nancy E Hynes "
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Tyrosine kinase signalling in breast cancer
Nancy E Hynes
Breast Cancer Research , 2000, DOI: 10.1186/bcr48
Abstract: Receptors of the tyrosine kinase family play an important role in the integration and interpretation of diverse extracellular stimuli, allowing a cell to respond appropriately to its environment. All members of this superfamily have in common an extracellular ligand-binding domain, a single membrane-spanning region and a cytoplasmic protein tyrosine kinase domain. Ligand binding promotes receptor dimerization, consequently stimulating kinase activity and triggering autophosphorylation of specific tyrosine residues within the cytoplasmic domain (for review [1]). These phosphorylated residues serve as docking sites for proteins that are involved in regulation of intracellular signalling cascades. The activation of RTKs is generally tightly controlled, allowing a normal cell to integrate external stimuli with internal signal transduction pathways correctly. In contrast, due to numerous molecular alterations that arise during the course of malignancy, a tumour is characterized by an abnormal response to its environment, which allows cancer cells to evade the normal mechanisms that control cellular proliferation.Alterations in RTK expression and activation, and in the signalling molecules that lie downstream of the receptors play important roles in the development of cancer. This topic is the major focus of the thematic review section of the present issue of Breast Cancer Research. In particular, Stern [2] writes on the interactions among the ErbB family members [epidermal growth factor (EGF) receptor, ErbB2, ErbB3 and ErbB4]; Andrechek and Muller [3] present information gleaned from transgenic models of mammary cancer developed with Neu, the rat ErbB2 equivalent; and Prenzel et al [4] describe the emerging role of the EGF receptor as an integrator for other classes of membrane receptors. The non-RTK Src is hyperactive in breast cancer and, as discussed in the review by Biscardi et al [5], there is a cooperative interaction between Src and the EGF receptor, which very li
Key signalling nodes in mammary gland development and cancer: Myc
Nancy E Hynes, Tina Stoelzle
Breast Cancer Research , 2009, DOI: 10.1186/bcr2406
Abstract: Since the early 1980s, numerous investigations have focused on c-Myc to explore its role in normal organ physiology, as well as in tumor biology [1,2]. The focus of the present review, c-Myc (hereafter referred to as Myc), is the cellular homolog of the avian retroviral oncogene v-myc and, together with N-myc and L-myc, comprises the family of myc proto-oncogenes. The half-lives of Myc mRNA and protein are short, allowing for tight and rapid regulation of Myc levels, which occurs via numerous transcription factors (TFs) and signaling pathways. Proteins that directly bind the promoter or indirectly influence promoter activity have been reviewed recently [3]. To provide some insight into the complexity of Myc regulation, we will mention a few of the factors and pathways that impact on its expression, many of which were shown to be essential during mammary gland development [4].The myc promoter contains TF binding sites for Myc (auto-suppression), estrogen receptor (ER) alpha, T-cell factor (TCF) 4, Notch/C promoter-binding factor 1 (Cbf1), E2F, Fos/Jun, signal transducer and activator of transcription (Stat) 3, NF-κB, Smads and others. TFs that occupy or regulate the myc promoter without specific binding sites include p53, CCAAT/enhancer binding protein beta, and Stat5. Moreover, numerous signaling pathways that are frequently deregulated in human cancer influence myc expression; for example, rat sarcoma (Ras)/extracellular signal-related kinase (Erk) and phosphoinositide 3-kinase (PI3K)/serine/threonine kinase Akt (Akt). Post-translational modifications of Myc include phos-phorylation, ubiquitinylation and acetylation, and their effects on Myc activity have been reviewed [5].The Myc protein is a basic helix-loop-helix TF that must heterodimerize with the abundantly expressed Max to regulate transcription. Myc-Max dimers bind to hexameric DNA sequences (E-box) and activate transcription by recruiting multiple coactivators [1]. In contrast, when dimerized with basic he
BAD: a good therapeutic target?
Andrea B Motoyama, Nancy E Hynes
Breast Cancer Research , 2002, DOI: 10.1186/bcr552
Abstract: Cells are naturally endowed with mechanisms that induce apoptosis, a characteristic that underlies the successful use of standard cancer drugs and radiation. The growth of a tumor, however, is exquisitely dependent upon overcoming the normal tendency of a cell to die under stress conditions. A major clinical problem is thus the ability of malignant cells to evade cancer drugs, either by altering expression of surveillance molecules or by upregulating signaling pathways capable of promoting cell survival and proliferation, even in the presence of an apoptosis-inducing agent.A recent paper from the laboratory of Charles Streuli described the ability of ZD1839, a small-molecule inhibitor of the epidermal growth factor receptor (EGFR), to induce apoptosis of normal mammary cells [1]. In this system, insulin-like growth factor-1 (IGF-1) and epidermal growth factor (EGF) are two important survival factors. Interestingly, ZD1839 was effective in inducing cell death not only in the presence of EGF, but also in the presence of IGF-1. Furthermore, the authors shed light on the mechanisms underlying ZD1839-mediated apoptosis, showing that BAD, a BCL-2 family member, is an important survival target of the EGFR in mammary cells. The results are promising, considering the importance of this receptor in breast cancer development. In the future, it will be essential to understand the mechanisms by which apoptosis can be triggered in tumors in order to achieve the desired efficacy in cancer therapeutics.Members of the ErbB family of receptor tyrosine kinases play important roles in normal biology of the breast and in cancer. Upon ligand binding to the extracellular domain, these receptors form homodimers and heterodimers leading to activation of the intracellular kinase domain and phosphorylation on specific tyrosine residues. These tyrosines then serve as docking sites for molecules that further transduce the signal, leading to activation of the mitogen-activated protein kinase (MA
c-Myc affects mRNA translation, cell proliferation and progenitor cell function in the mammary gland
Tina Stoelzle, Patrick Schwarb, Andreas Trumpp, Nancy E Hynes
BMC Biology , 2009, DOI: 10.1186/1741-7007-7-63
Abstract: Generation of c-mycfl/fl mice carrying the mammary gland-specific WAPiCre transgene resulted in c-Myc loss in alveolar epithelial cells starting in mid-pregnancy. Three major phenotypes were observed in glands of mutant mice. First, c-Myc-deficient alveolar cells had a slower proliferative response at the start of pregnancy, causing a delay but not a block of alveolar development. Second, while milk composition was comparable between wild type and mutant animals, milk production was reduced in mutant glands, leading to slower pup weight-gain. Electron microscopy and polysome fractionation revealed a general decrease in translational efficiency. Furthermore, analysis of mRNA distribution along the polysome gradient demonstrated that this effect was specific for mRNAs whose protein products are involved in milk synthesis. Moreover, quantitative reverse transcription-polymerase chain reaction analysis revealed decreased levels of ribosomal RNAs and ribosomal protein-encoding mRNAs in mutant glands. Third, using the mammary transplantation technique to functionally identify alveolar progenitor cells, we observed that the mutant epithelium has a reduced ability to repopulate the gland when transplanted into NOD/SCID recipients.We have demonstrated that c-Myc plays multiple roles in the mouse mammary gland during pregnancy and lactation. c-Myc loss delayed, but did not block proliferation and differentiation in pregnancy. During lactation, lower levels of ribosomal RNAs and proteins were present and translation was generally decreased in mutant glands. Finally, the transplantation studies suggest a role for c-Myc in progenitor cell proliferation and/or survival.See related minireview by Evan et al: http://jbiol.com/content/8/8/77 webciteThe oncoprotein c-Myc is a basic helix-loop-helix transcription factor implicated in multiple cellular processes, including proliferation, differentiation, metabolism, and apoptosis (reviewed in Eilers and Eisenman [1]). c-Myc regulates RN
MHO1, an Evolutionarily Conserved Gene, Is Synthetic Lethal with PLC1; Mho1p Has a Role in Invasive Growth
Ivan D. Schlatter, Maria Meira, Vanessa Ueberschlag, Dominic Hoepfner, Rao Movva, Nancy E. Hynes
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0032501
Abstract: The novel protein Memo (Mediator of ErbB2 driven cell motility) was identified in a screen for ErbB2 interacting proteins and found to have an essential function in cell motility. Memo is evolutionarily conserved with homologs found in all branches of life; the human and yeast proteins have a similarity of >50%. In the present study we used the model organism S. cerevisiae to characterize the Memo-homologue Mho1 (Yjr008wp) and to investigate its function in yeast. In a synthetic lethal screen we found MHO1 as a novel synthetic lethal partner of PLC1, which encodes the single phospholipase C in yeast. Double-deleted cells lacking MHO1 and PLC1, proliferate for up to ten generations. Introduction of human Memo into the memoΔplc1Δ strain rescued the synthetic lethal phenotype suggesting that yeast and human proteins have similar functions. Mho1 is present in the cytoplasm and the nucleus of yeast cells; the same distribution of Memo was found in mammalian cells. None of the Memo homologues have a characteristic nuclear localization sequence, however, a conserved nuclear export sequence is found in all. In mammalian cells, blocking nuclear export with Leptomycin B led to nuclear Memo accumulation, suggesting that it is actively exported from the nucleus. In yeast MHO1 expression is induced by stress conditions. Since invasive growth in S. cerevisiea is also stress-induced, we tested Mho1's role in this response. MHO1 deletion had no effect on invasion induced by nutrient deprivation, however, Mho1 overexpression blocked the invasive ability of yeast cells, suggesting that Mho1 might be acting in a dominant negative manner. Taken together, our results show that MHO1 is a novel synthetic lethal interactor with PLC1, and that both gene products are required for proliferation. Moreover, a role for Memo in cell motility/invasion appears to be conserved across species.
Autocrine WNT signaling contributes to breast cancer cell proliferation via the canonical WNT pathway and EGFR transactivation
Thomas Schlange, Yutaka Matsuda, Susanne Lienhard, Alexandre Huber, Nancy E Hynes
Breast Cancer Research , 2007, DOI: 10.1186/bcr1769
Abstract: Using the WNT modulator sFRP1 and short interfering RNA-mediated Dishevelled (DVL) knockdown, we interfered with autocrine WNT signaling at the ligand-receptor level. The impact on proliferation was measured by cell counting, YOPRO, and the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) assay; β-catenin, EGFR, ERK1/2 activation, and PARP (poly [ADP-ribose]polymerase) cleavages were assessed by Western blotting after treatment of human breast cancer cell lines with conditioned media, purified proteins, small-molecule inhibitors, or blocking antibodies.Phospho-DVL and stabilized β-catenin are present in many breast tumor cell lines, indicating autocrine WNT signaling activity. Interfering with this loop decreases active β-catenin levels, lowers ERK1/2 activity, blocks proliferation, and induces apoptosis in MDA-MB-231, BT474, SkBr3, JIMT-1, and MCF-7 cells. The effects of WNT signaling are mediated partly by EGFR transactivation in human breast cancer cells in a metalloprotease- and Src-dependent manner. Furthermore, Wnt1 rescues estrogen receptor-positive (ER+) breast cancer cells from the anti-proliferative effects of 4-hydroxytamoxifen (4-HT) and this activity can be blocked by an EGFR tyrosine kinase inhibitor.Our data show that interference with autocrine WNT signaling in human breast cancer reduces proliferation and survival of human breast cancer cells and rescues ER+ tumor cells from 4-HT by activation of the canonical WNT pathway and EGFR transactivation. These findings suggest that interference with WNT signaling at the ligand-receptor level in combination with other targeted therapies may improve the efficiency of breast cancer treatments.Growth factors of the wingless and integration site growth factor (WNT) family are secreted, glycosylated, and palmitoylated peptides that interact with seven-transmembrane receptors of the Frizzled (FZD) family. Diverse signaling pathways are activated upon WNT/FZD binding. The ligand/receptor interac
WNT signaling enhances breast cancer cell motility and blockade of the WNT pathway by sFRP1 suppresses MDA-MB-231 xenograft growth
Yutaka Matsuda, Thomas Schlange, Edward J Oakeley, Anne Boulay, Nancy E Hynes
Breast Cancer Research , 2009, DOI: 10.1186/bcr2317
Abstract: The breast cancer cell line MDA-MB-231 was used to study WNT signaling. We examined the effects of activating or blocking the WNT pathway on cell motility by treatment with WNT ligands or by ectopic sFPR1 expression, respectively. The ability of sFRP1-expressing MDA-MB-231 cells to grow as xenografts was also tested. Microarray analyses were carried out to identify targets with roles in MDA-MB-231/sFRP1 tumor growth inhibition.We show that WNT stimulates the migratory ability of MDA-MB-231 cells. Furthermore, ectopic expression of sFRP1 in MDA-MB-231 cells blocks canonical WNT signaling and decreases their migratory potential. Moreover, the ability of MDA-MB-231/sFRP1-expressing cells to grow as xenografts in mammary glands and to form lung metastases is dramatically impaired. Microarray analyses led to the identification of two genes, CCND1 and CDKN1A, whose expression level is selectively altered in vivo in sFRP1-expressing tumors. The encoded proteins cyclin D1 and p21Cip1 were downregulated and upregulated, respectively, in sFRP1-expressing tumors, suggesting that they are downstream mediators of WNT signaling.Our results show that the WNT pathway influences multiple biological properties of MDA-MB-231 breast cancer cells. WNT stimulates tumor cell motility; conversely sFRP1-mediated WNT pathway blockade reduces motility. Moreover, ectopic sFRP1 expression in MDA-MB-231 cells has a strong negative impact on tumor outgrowth and blocked lung metastases. These results suggest that interference with WNT signaling using sFRP1 to block the ligand- receptor interaction may be a valid therapeutic approach in breast cancer.The WNT signaling network is complex, with 19 WNT ligands, 10 Frizzled (FZD) receptors, as well as the co-receptors, low-density lipoprotein receptor-related protein (LRP) 5 and LRP6. WNT receptor binding stimulates intracellular signaling, promoting stabilization and nuclear translocation of the key effector of the canonical pathway, β-catenin [1,2].
Combinatorial targeting of FGF and ErbB receptors blocks growth and metastatic spread of breast cancer models
Amine Issa, Jason W Gill, Marinus R Heideman, Ozgur Sahin, Stefan Wiemann, Julien H Dey, Nancy E Hynes
Breast Cancer Research , 2013, DOI: 10.1186/bcr3379
Abstract: Using 4T1 or 67NR models of basal-like breast cancer, tumor growth was measured in mice treated with an FGFR inhibitor (dovitinib/TKI258), a PI3K/mTOR inhibitor (NVP-BEZ235) or a pan-ErbB inhibitor (AEE788) individually or in combination. To uncover mechanisms underlying inhibitor action, signaling pathway activity was examined in tumor lysates and transcriptome analysis carried out to identify pathways upregulated by FGFR inhibition. Anti-phosphotyrosine receptor antibody arrays (P-Tyr RTK) were also used to screen 4T1 tumors.The combination of dovitinib + NVP-BEZ235 causes tumor stasis and strong down-regulation of the FRS2/Erk and PI3K/Akt/mTOR signaling pathways. P-Tyr RTK arrays identified high levels of P-EGFR and P-ErbB2 in 4T1 tumors. Testing AEE788 in the tumor models revealed that the combination of dovitinib + AEE788 resulted in blockade of the PI3K/Akt/mTOR pathway, prolonged tumor stasis and in the 4T1 model, a significant decrease in lung metastasis. The results show that in vivo these breast cancer models become dependent upon co-activation of FGFR and ErbB receptors for PI3K pathway activity.The work presented here shows that in the breast cancer models examined, the combination of dovitinib + NVP-BEZ235 or dovitinib + AEE788 results in strong inhibition of tumor growth and a block in metastatic spread. Only these combinations strongly down-regulate the FGFR/FRS2/Erk and PI3K/Akt/mTOR signaling pathways. The resultant decrease in mitosis and increase in apoptosis was consistently stronger in the dovitinib + AEE788 treatment-group, suggesting that targeting ErbB receptors has broader downstream effects compared to targeting only PI3K/mTOR. Considering that sub-classes of human breast tumors co-express ErbB receptors and FGFRs, these results have implications for targeted therapy.Members of the receptor tyrosine kinase (RTK) superfamily are often aberrantly expressed and/or activated in human tumors and many have been successfully targeted using antibo
Co-expression of HER2 and HER3 receptor tyrosine kinases enhances invasion of breast cells via stimulation of interleukin-8 autocrine secretion
Nicola Aceto, Stephan Duss, Gwen MacDonald, Dominique S Meyer, Tim-C Roloff, Nancy E Hynes, Mohamed Bentires-Alj
Breast Cancer Research , 2012, DOI: 10.1186/bcr3329
Abstract: Three-dimensional (3D) cultures, invasion and migration assays were used to determine the effects of HER2 and HER3 co-expression and activation. Gene expression analysis was performed to identify the gene network induced by HER2/HER3 in 3D cultures. Bioinformatic analysis and neutralizing antibodies were used to identify key mediators of HER2/HER3-evoked invasion.Co-expression of the tyrosine kinase receptors HER2 and HER3 induced migration and invasion of MCF10A cells. Microarray analysis of these cells revealed a specific "HER2/HER3 signature" comprising 80 upregulated transcripts, with IL8 being the highest (11-fold upregulation). Notably, examination of public datasets revealed high levels of IL8 transcripts in HER2-enriched as well as basal-like primary breast tumors, two subtypes characterized by a particularly poor prognosis. Moreover, IL8 expression correlated with high tumor grade and ER-negative status. Importantly, treatment with IL8-neutralizing antibodies prevented invasion of MCF10A-HER2/HER3 and BT474 cells in 3D cultures, highlighting the importance of IL8 autocrine signaling upon HER2/HER3 activation.Our findings demonstrate that HER2 and HER3 co-expression induces IL8 autocrine signaling, leading to the invasion of mammary cells. Agents targeting IL8 or its receptor CXCR1 may be useful for the treatment of HER2/HER3/IL8-positive breast cancers with invasive traits.HER2 (ErbB2) and HER3 (ErbB3) are members of a family of four receptor tyrosine kinases that also includes the epidermal growth factor receptor (HER1/EGFR) and HER4 (ErbB4) [1]. HER2 overexpression accounts for approximately 20% of all breast cancers and is commonly associated with a poor prognosis [2]. The importance of HER2 in cancer is highlighted by the clinical efficacy of the anti-HER2 humanized monoclonal antibody trastuzumab (Herceptin), especially when combined with chemotherapy, for the treatment of HER2-overexpressing breast cancers [3,4]. HER3 has been strongly implicated as a
Memo Has a Novel Role in S1P Signaling and Crucial for Vascular Development
Shunya Kondo, Alessia Bottos, Jeremy C. Allegood, Regis Masson, Francisca G. Maurer, Christel Genoud, Patrick Kaeser, Andrea Huwiler, Masato Murakami, Sarah Spiegel, Nancy E. Hynes
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0094114
Abstract: Memo is a conserved protein that was identified as an essential mediator of tumor cell motility induced by receptor tyrosine kinase activation. Here we show that Memo null mouse embryonic fibroblasts (MEFs) are impaired in PDGF-induced migration and this is due to a defect in sphingosine-1-phosphate (S1P) signaling. S1P is a bioactive phospholipid produced in response to multiple stimuli, which regulates many cellular processes. S1P is secreted to the extracellular milieu where it exerts its function by binding a family of G-protein coupled receptors (S1PRs), causing their activation in an autocrine or paracrine manner. The process, termed cell-autonomous S1PR signaling, plays a role in survival and migration. Indeed, PDGF uses cell-autonomous S1PR signaling to promote cell migration; we show here that this S1P pathway requires Memo. Using vascular endothelial cells (HUVECs) with Memo knock-down we show that their survival in conditions of serum-starvation is impaired. Furthermore, Memo loss in HUVECs causes a reduction of junctional VE-cadherin and an increase in sprout formation. Each of these phenotypes is rescued by S1P or S1P agonist addition, showing that Memo also plays an important role in cell-autonomous S1PR signaling in endothelial cells. We also produced conventional and endothelial cell-specific conditional Memo knock-out mouse strains and show that Memo is essential for embryonic development. Starting at E13.5 embryos of both strains display bleeding and other vascular problems, some of the phenotypes that have been described in mouse strains lacking S1PRs. The essential role of Memo in embryonic vascular development may be due in part to alterations in S1P signaling. Taken together our results show that Memo has a novel role in the S1P pathway and that Memo is needed to promote cell-autonomous S1PR activation.
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