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Biomedical subjects

Nancy E Hynes

Publications and source records attributed to Nancy E Hynes.

At least 19 recordsLinked to original sources
PubMed2006

Novel c-MYC target genes mediate differential effects on cell proliferation and migration.

The developmental and oncogenic roles of MYC proteins are well established, but the transcriptional targets mediating their functions remain elusive. Using small interfering RNA-mediated knockdown in breast and cervix carcinoma cell lines, which overexpress c-MYC, we show that c-MYC independently controls metabolism and cell proliferation, and can, depending on the cells, promote or inhibit migration. We identified new c-MYC target genes in these cell lines, and show that selective regulation of some targets correlates with the phenotypic responses of these different cell lines to c-MYC depletion. Notably, we show that a positive regulation of the WNT signalling pathway contributes to c-MYC pro-mitogenic effects in breast and cervix carcinoma cells. We also show that repression of CCL5/RANTES accounts for c-MYC anti-migratory effects in specific breast cancer cells. Our combined genomic and phenotypic analysis indicates that c-MYC functions are cellular-context-dependent and that selectively regulated genes are responsible for its differential properties.

Cell Line, Tumor↗
PubMed2006

The mTOR pathway in breast cancer.

There is currently a wealth of information regarding the mutations that contribute to cancer development. Most of these mutations alter the expression and activity of signal transduction proteins. The current goal in cancer therapy is to use our knowledge of the molecular alterations in a cancer cell to choose the most appropriate signal transduction inhibitor for an individual patient. The topic of this review is the mammalian target of rapamycin (mTOR) kinase signaling pathway, which is aberrantly activated in many types of human cancer. We will discuss the mTOR pathway and the potential mechanisms that contribute to its activation in cancer, together with data relating to the potential for inhibitors targeting the mTOR-signaling pathway to impact on breast cancer therapy.

Antibiotics, Antineoplastic↗
PubMed2006

Targeting ADAMS and ERBBs in lung cancer.

Aberrant ERBB receptor activity contributes to the development of many human cancers. Receptor overexpression, kinase domain (KD) mutations, and autocrine ligand production contribute to ERBB activation in human tumors. ERBB-targeted tyrosine kinase inhibitors (TKIs) and monoclonal antibodies are used in cancer treatment; however, clinical hurdles, including patient selection and TKI resistance, need to be overcome in order to optimize therapy. This minireview will discuss recent findings on possible mechanisms leading to ERBB-targeted therapy resistance and potential means to overcome them.

ADAM Proteins↗
PubMed2005

Ablation of beta1 integrin in mammary epithelium reveals a key role for integrin in glandular morphogenesis and differentiation.

Integrin-mediated adhesion regulates the development and function of a range of tissues; however, little is known about its role in glandular epithelium. To assess the contribution of beta1 integrin, we conditionally deleted its gene in luminal epithelia during different stages of mouse mammary gland development and in cultured primary mammary epithelia. Loss of beta1 integrin in vivo resulted in impaired alveologenesis and lactation. Cultured beta1 integrin-null cells displayed abnormal focal adhesion function and signal transduction and could not form or maintain polarized acini. In vivo, epithelial cells became detached from the extracellular matrix but remained associated with each other and did not undergo overt apoptosis. beta1 integrin-null mammary epithelial cells did not differentiate in response to prolactin stimulation because of defective Stat5 activation. In mice where beta1 integrin was deleted after the initiation of differentiation, fewer defects in alveolar morphology occurred, yet major deficiencies were also observed in milk protein and milk fat production and Stat5 activation, indicating a permissive role for beta1 integrins in prolactin signaling. This study demonstrates that beta1 integrin is critical for the alveolar morphogenesis of a glandular epithelium and for maintenance of its differentiated function. Moreover, it provides genetic evidence for the cooperation between integrin and cytokine signaling pathways.

Animals↗
PubMed2005

The antitumor and antiangiogenic activity of vascular endothelial growth factor receptor inhibition is potentiated by ErbB1 blockade.

PURPOSE: Receptor tyrosine kinases of the ErbB family play important roles in the control of tumor growth. Vascular endothelial growth factor (VEGF) stimulates endothelial cell proliferation, enhances vascular permeability, and plays an important role in tumor vascularization. We evaluated the effects of selective VEGF receptor (VEGFR; PTK787/ZK222584) and ErbB (PKI166 and ZD1839) inhibitors on tumor growth and angiogenesis and asked whether additional therapeutic benefit was conferred by combination treatment. EXPERIMENTAL DESIGN: The antitumor activity of each inhibitor alone or in combination was assessed in human cancer models in immunocompromised mice. ErbB receptor expression and activation of downstream signaling pathway was evaluated in both tumor and endothelial cells. RESULTS: Both ErbB inhibitors significantly enhanced the antitumor activity of PTK787/ZK222584. In vitro, ErbB1 inhibition blocked VEGF release by tumor cells and proliferation of both tumor and endothelial cells. In an in vitro angiogenesis assay, epidermal growth factor (EGF) stimulated the release of VEGF by smooth muscle cells resulting in increased angiogenesis, a response blocked by administration of PTK787/ZK222584. Under basal condition, both ZD1839 and PTK787/ZK222584 blocked sprouting, likely via inhibition of an autocrine ErbB1 loop and VEGFR signaling, respectively, in endothelial cells. In conditions of limiting VEGF, EGF plays an important role in endothelial cell proliferation, survival, and sprouting. CONCLUSION: We have shown that activation of ErbB1 triggers a plethora of effects, including direct effects on tumor and endothelial cells and indirect effects mediated via induction of VEGF release. Simultaneous blockade of ErbB1 and VEGFR pathways results in a cooperative antitumor effect, indicating that this combination may represent a valid therapeutic strategy.

Angiogenesis Inhibitors↗
PubMed2005

Beta1 integrins regulate mammary gland proliferation and maintain the integrity of mammary alveoli.

Integrin-extracellular matrix interactions play important roles in the coordinated integration of external and internal cues that are essential for proper development. To study the role of beta1 integrin in the mammary gland, Itgbeta1(flox/flox) mice were crossed with WAPiCre transgenic mice, which led to specific ablation of beta1 integrin in luminal alveolar epithelial cells. In the beta1 integrin mutant mammary gland, individual alveoli were disorganized resulting from alterations in cell-basement membrane associations. Activity of focal adhesion kinase (FAK) was also decreased in mutant mammary glands. Luminal cell proliferation was strongly inhibited in beta1 integrin mutant glands, which correlated with a specific increase of p21 Cip1 expression. In a p21 Cip1 null background, there was a partial rescue of BrdU incorporation, providing in vivo evidence linking p21 Cip1 to the proliferative defect observed in beta1 integrin mutant glands. A connection between p21 Cip1 and beta1 integrin as well as FAK was also established in primary mammary cells. These results point to the essential role of beta1 integrin signaling in mammary epithelial cell proliferation.

Animals↗
PubMed2005

ERBB4/HER4 potentiates STAT5A transcriptional activity by regulating novel STAT5A serine phosphorylation events.

The epidermal growth factor receptor family member ERBB4 is required for mammary gland development and lactation. ERBB4 activities in the breast are mediated through the signal transducer and activator of transcription (STAT) family member STAT5A, and ERBB4 directly activates STAT5A, in part, through phosphorylation of STAT5A at the regulatory Tyr-694. Here we show that STAT5A regulation by ERBB4 is also mediated through STAT5A serine phosphorylation. Using a reverse-phase high performance liquid chromatography tandem mass spectrometry analysis of proteolytically digested STAT5A coexpressed with ERBB4, we identified STAT5A serine phosphorylations at the previously described Ser-779 and at the novel Ser-127/Ser-128. Immunohistochemistry of wild-type and ERBB4-null mammary glands at late pregnancy showed that ERBB4 expression was required for STAT5A phosphorylation at Ser-779. Independent serine-to-alanine residue substitutions in full-length STAT5A revealed that although STAT5A Ser-779 phosphorylation was dispensable for phosphorylation of STAT5A at Tyr-694 and subsequent DNA binding, Ser-779 was required to stabilize an interaction with ERBB4 and mediate ERBB4-induced STAT5A stimulation of gene expression. STAT5A Ser-127/Ser-128, on the other hand, was required for ERBB4-induced phosphorylation of Tyr-694, whereas Ser-779 and as yet unidentified tyrosine residues were phosphorylated in the absence of Ser-127/Ser-128. In addition, STAT5A S127A/S128A remained associated with ERBB4 but failed to bind DNA or activate transcription in response to ERBB4 coexpression. Our studies demonstrate that phosphorylation of STAT5A at Ser-127/Ser-128 and Ser-779 are obligatory events regulating ERBB4-mediated activation of STAT5A.

Amino Acid Sequence↗
PubMed2005

ERBB receptors and cancer: the complexity of targeted inhibitors.

ERBB receptor tyrosine kinases have important roles in human cancer. In particular, the expression or activation of epidermal growth factor receptor and ERBB2 are altered in many epithelial tumours, and clinical studies indicate that they have important roles in tumour aetiology and progression. Accordingly, these receptors have been intensely studied to understand their importance in cancer biology and as therapeutic targets, and many ERBB inhibitors are now used in the clinic. We will discuss the significance of these receptors as clinical targets, in particular the molecular mechanisms underlying response.

Animals↗
PubMed2004

Cooperation between fibroblast growth factor receptor-4 and ErbB2 in regulation of cyclin D1 translation.

Alterations in ErbB2 or fibroblast growth factor receptor-4 (FGFR-4) expression and activity occur in a significant fraction of breast cancers. Because signaling molecules and pathways cooperate to drive cancer progression, simultaneous targeting of multiple pathways is an appealing therapeutic strategy. With this in mind, we examined breast tumor cells for their sensitivity to the ErbB2 and FGFR inhibitors, PKI166 and PD173074, respectively. Simultaneous blocking of ErbB2 and FGFR-4 in MDA-MB-453 tumor cells had a stronger anti-proliferative effect than treatment with individual inhibitors. Examination of cell cycle regulators revealed a novel translation-mediated mechanism whereby ErbB2 and FGFR-4 cooperate to regulate cyclin D1 levels. Our results showed that FGFR-4 and ErbB2 via the MAPK and the phosphatidylinositol 3-kinase/protein kinase B pathways, respectively, both contribute to the maintenance of constitutive activity of the mammalian target of rapamycin translational pathway. Dual inhibition of these receptors strongly blocked S6 kinase 1 (S6K1) activity and cyclin D1 translation, as attested by a decrease in cyclin D1 mRNA association with polysomes. Ectopic expression of active protein kinase B or active S6K1 abrogated the dual inhibitor-mediated down-regulation of cyclin D1 expression, demonstrating the importance of these FGFR-4/ErbB2 signaling targets in regulating cyclin D1 translation. S6K1 has the central role in this process, since small interfering RNA-targeted S6K1 depletion led to a decrease in cellular S6K1 activity and, as a consequence, repression of cyclin D1 expression. Thus, we propose a novel mechanism for controlling cyclin D1 expression downstream of combined activity of ErbB2 and FGFR-4 that involves S6K1-mediated translation.

Breast Neoplasms↗
PubMed2004

TEL/ETV6 is a signal transducer and activator of transcription 3 (Stat3)-induced repressor of Stat3 activity.

The signal transducer and activator of transcription 3 (Stat3) transcription factor is required for the antiproliferative effects induced by cytokines, such as the interleukin-6 type. In order to investigate the role of Stat3 in inhibition of cell proliferation, we have used an inducible Stat3 construct in A375 melanoma cells. We found that activation of Stat3 to moderate levels was sufficient to repress A375 proliferation, by slowing cell transit through the cell cycle. Enhanced and prolonged Stat3 activity led to cell cycle arrest and apoptosis. Genes whose expression was altered by Stat3 activation were identified by oligonucleotide microarray analysis. We found that TEL (ETV6), a novel Stat3 target identified in this study, is a negative regulator of Stat3 activity. Small interfering RNA-mediated inhibition of TEL expression resulted in increased Stat3-dependent transcriptional activity and stronger Stat3 antiproliferative activity. Confirming these results, overexpression of TEL repressed Stat3 transcriptional activity. Intriguingly, Stat3 repression did not require TEL DNA binding and appeared to proceed via recruitment of TEL to Stat3. Inhibition of Stat3 activity by TEL represents a novel mechanism regulating the Stat3 signaling pathway.

Blotting, Western↗
PubMed2004

Memo mediates ErbB2-driven cell motility.

Clinical studies have revealed that cancer patients whose tumours have increased ErbB2 expression tend to have more aggressive, metastatic disease, which is associated with parameters predicting a poor outcome. The molecular basis underlying ErbB2-dependent cell motility and metastases formation, however, still remains poorly understood. In this study, we show that activation of a set of signalling molecules, including MAPK, phosphatidylinositol-3-OH kinase (PI(3)K) and Src, is required for Neu/ErbB2-dependent lamellipodia formation and for motility of breast carcinoma cells. Stimulation of these molecules, however, failed to induce efficient cell migration in the absence of Neu/ErbB2 phosphorylation at Tyr 1201 or Tyr 1227. We describe a novel molecule, Memo (mediator of ErbB2-driven cell motility), that interacts with a phospho-Tyr 1227-containing peptide, most probably through the Shc adaptor protein. After Neu/ErbB2 activation, Memo-defective cells form actin fibres and grow lamellipodia, but fail to extend microtubules towards the cell cortex. Our data suggest that Memo controls cell migration by relaying extracellular chemotactic signals to the microtubule cytoskeleton.

Actin Cytoskeleton↗
PubMed2004

Blocking of FGFR signaling inhibits breast cancer cell proliferation through downregulation of D-type cyclins.

Overexpression of fibroblast growth factor receptor (FGFR) tyrosine kinases has been found in many human breast cancers and has been associated with poor patient prognosis. In order to understand the mechanism by which FGFR mediates breast cancer cell proliferation, we used a low molecular weight compound, PD173074, that selectively inhibits FGFR tyrosine kinase activity and autophosphorylation. This potential anticancer agent caused a G1 growth arrest of MDA-MB-415, MDA-MB-453 and SUM 52 breast cancer cells. Our analyses revealed that FGFR signaling links to the cell cycle machinery via D-type cyclins. PD173074-mediated inhibition of FGFR activity caused downregulation of cyclin D1 and cyclin D2 expression, inhibition of cyclin D/cdk4 activity and, as a consequence, reduction of pRB phosphorylation. Retroviral-mediated ectopic expression of cyclin D1 prevented pRB hypophosphorylation and the cell cycle G1 block in PD173074-treated cells, suggesting a central role for D cyclins in proliferation of FGFR-driven breast cancer cells. The repression of FGFR activity caused downregulation of MAPK in MDA-MB-415 and MDA-MB-453 cells. In SUM 52 cells, both MAPK and PI3K signaling pathways were suppressed. In conclusion, results shown here describe a mechanism by which FGFR promotes proliferation of breast cancer cells.

Breast Neoplasms↗
PubMed2004

A new therapeutic antibody masks ErbB2 to its partners.

In cancer cells, the ErbB2 receptor tyrosine kinase can be activated in two ways: by overexpression or by ligand-mediated stimulation of another ErbB receptor. The ErbB2-targeting antibody trastuzumab (Herceptin) is used for treatment of metastatic breast cancer patients whose tumors overexpress ErbB2. A new structural study in this issue of Cancer Cell reveals how targeting ErbB2 with another antibody, pertuzumab (Omnitarg), prevents ligand-induced dimerization of ErbB2 with the other ErbB receptors. Pertuzumab's novel mode of action might offer additional therapeutic opportunities for treatment of tumors expressing ligand-activated ErbB2.

Antibodies, Monoclonal↗
PubMed2004

ErbB receptors: directing key signaling networks throughout life.

The epidermal growth factor (EGF)-related peptides bind the ErbB receptors, inducing the formation of different homo- and heterodimers. Receptor dimerization promotes activation of the intrinsic kinase, leading to phosphorylation of specific tyrosines located in the ErbB's cytoplasmic region. These phosphorylated residues serve as docking sites for a variety of signaling molecules whose recruitment stimulates intracellular signaling cascades, which ultimately control diverse genetic programs. Particular ligand-receptor complexes have essential roles in embryonic development as well as in the adult. Finally, ErbB receptors are being pursued as therapeutic targets because aberrant ErbB activity has been observed in many human cancers. In this review, we discuss these data in more detail, illustrating the importance of tightly regulated ErbB signaling throughout life.

Aging↗
PubMed2003

The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation.

ErbB2 is a receptor tyrosine kinase whose activity in normal cells depends on dimerization with another ligand-binding ErbB receptor. In contrast, amplification of c-erbB2 in tumors results in dramatic overexpression and constitutive activation of the receptor. Breast cancer cells overexpressing ErbB2 depend on its activity for proliferation, because treatment of these cells with ErbB2-specific antagonistic antibodies or kinase inhibitors blocks tumor cells in the G1 phase of the cell cycle. Intriguingly, loss of ErbB2 signaling is accompanied by a decrease in the phosphotyrosine content of ErbB3. On the basis of these results, it has been proposed that ErbB3 might be a partner for ErbB2 in promoting cellular transformation. To test this hypothesis and directly examine the role of the "kinase dead" ErbB3, we specifically ablated its expression with a designer transcription factor (E3). By infection of ErbB2-overexpressing breast cancer cells with a retrovirus expressing E3, we show that ErbB3 is an essential partner in the transformation process. Loss of functional ErbB2 or ErbB3 has similar effects on cell proliferation and cell cycle regulators. Furthermore, expression of constitutively active protein kinase B rescues the proliferative block induced as a consequence of loss of ErbB2 or ErbB3 signaling. These results demonstrate that ErbB2 overexpression and activity alone are insufficient to promote breast tumor cell division. Furthermore, we identify ErbB3's role, which is to couple active ErbB2 to the phosphatidylinositol 3-kinase/protein kinase B pathway. Thus, the ErbB2/ErbB3 dimer functions as an oncogenic unit to drive breast tumor cell proliferation.

Breast Neoplasms↗
PubMed2003

ErbB1 and prostate cancer: ErbB1 activity is essential for androgen-induced proliferation and protection from the apoptotic effects of LY294002.

BACKGROUND: Androgens play a critical role in proliferation and survival of prostate cancer cells, but the mechanisms leading to these effects are poorly understood. ErbB receptor tyrosine kinases have been implicated in the development of prostate cancer. METHODS: We examined the interaction between the ErbB receptors and androgens using the LNCaP androgen-sensitive prostate tumor model. RESULTS: In the absence of androgens, the cells have low levels of ErbB1 and relatively high levels of ErbB2. Addition of androgens to the medium reversed the ratio; ErbB1 levels rose and ErbB2 levels dropped in response to treatment with the synthetic hormone, R1881. Expression of ErbB activating ligands was found to be constitutive and androgen-independent. The androgen-induced proliferation of LNCaP cells was completely inhibited by the addition of the small molecule ErbB1 tyrosine kinase inhibitors CGP59326 and the bispecific inhibitor (PKI166) for ErbB1 and ErbB2 to the culture medium. Furthermore, in the absence of androgens the relatively low proliferative level was further significantly reduced in the presence of CGP59326. Inhibition of PI3K activity by LY294002 led to induction of apoptosis in androgen-deprived LNCaP cells. Androgen-mediated rescue from LY294002-induced apoptosis was inhibited by addition of CGP59326 to the cells. CONCLUSIONS: These results suggest a model whereby androgens promote an increase in the activity of the epidermal growth factor (EGF)-network by increasing ErbB1 levels, and this activity of is essential for androgen-induced proliferation and survival of the prostate cancer LNCaP cell line.

Androgens↗
PubMed2003

Tenascin-C blocks cell-cycle progression of anchorage-dependent fibroblasts on fibronectin through inhibition of syndecan-4.

Tenascin-C is an adhesion-modulatory extracellular matrix protein that is predominantly expressed during embryonic development, wound healing and in tumor stroma. Here we report that anchorage-dependent human, rat and mouse fibroblasts adhere poorly and fail to proliferate on pure tenascin-C. This was due to a significant reduction of cyclin-dependent kinase 2 (cdk2) activity, resulting from elevated expression and association of the cdk inhibitors (CKIs) p21Cip1 and p27Kip1. To analyse the effect of tenascin-C on fibronectin-mediated adhesion, cells were plated on a mixed fibronectin/tenascin-C substratum. Compared to fibronectin alone, cell spreading and adhesion signaling were compromised, as determined by delayed phosphorylation kinetics of focal adhesion kinase (FAK). Despite the presence of growth factors, these cells remained arrested in the G1 phase of the cell cycle. In contrast to cells plated on pure tenascin-C, cdk2 activity appeared to be inhibited independently of CKIs. Interestingly, overexpression of the transmembrane proteoglycan syndecan-4 restored cell spreading, adhesion signaling and DNA replication on the fibronectin/tenascin-C substratum. A similar rescue was observed using a recombinant peptide that spans the syndecan-4-binding site in fibronectin. This indicates that tenascin-C causes cell cycle arrest and cdk2 inactivation by interfering with fibronectin-syndecan-4 interactions. We therefore propose that syndecan-4 signaling plays a central role in the control of cellular proliferation of anchorage-dependent fibroblasts.

3T3 Cells↗