Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:O76050 (neu)
 3,969 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Nuclear Factor (NF)-kappaB family of transcription factors controls expression of genes which promote cell growth, survival, and neoplastic transformation. Recently we demonstrated aberrant constitutive activation of NF-kappaB in primary human and rat breast cancer specimens and in cell lines. Overexpression of the epidermal growth factor receptor (EGFR) family member Her-2/neu, seen in approximately 30% of breast cancers, is associated with poor prognosis. Previously, Her-2/neu has been shown to signal via a phosphatidylinositol 3 (PI3)-kinase to Akt/protein kinase B (PKB) pathway. Since this signaling pathway was recently shown to activate NF-kappaB, here we have tested the hypothesis that Her-2/neu can activate NF-kappaB in breast cancer. Overexpression of Her-2/neu and EGFR-4 in Ba/F3 cells led to constitutive PI3- and Akt kinase activities, and induction of classical NF-kappaB (p50/p65). Similarly, a tumor cell line and tumors derived from MMTV-Her-2/neu transgenic mice displayed elevated levels of classical NF-kappaB. Engagement of Her-2/neu receptor downregulated the level of NF-kappaB. NF-kappaB binding and activity in the cultured cells was reduced upon inhibition of the PI3- to Akt kinase signaling pathway via ectopic expression of kinase inactive mutants, incubation with wortmannin, or expression of the tumor suppressor phosphatase PTEN. Inhibitors of calpain, but not the proteasome, blocked IkappaB-alpha degradation. Inhibition of Akt did not affect IKK activity. These results indicate that Her-2/neu activates NF-kappaB via a PI3- to Akt kinase signaling pathway that can be inhibited via the tumor suppressor PTEN, and is mediated by calpain rather than the IkappaB kinase complex.
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PMID:Her-2/neu overexpression induces NF-kappaB via a PI3-kinase/Akt pathway involving calpain-mediated degradation of IkappaB-alpha that can be inhibited by the tumor suppressor PTEN. 1131 73

Nuclear factor-kappaB (NF-kappaB) is usually maintained in an inactive form in the cytoplasm through its association with inhibitor of kappaB (IkappaB) proteins, and is activated upon stimulation of cells with a variety of signals. However, constitutive activation of NF-kappaB is observed in a number of cancers including breast cancer. The signaling pathways that are involved in constitutive NF-kappaB activation remain largely unknown. Using breast cancer cell lines derived from transgenic mice that overexpress specific oncogene/growth factors in the mammary gland, we show that heregulin but not her2/neu, c-Myc or v-Ha-ras plays a major role in constitutive NF-kappaB activation. Her2/neu potentiated tumor necrosis factor alpha (TNFalpha)-inducible NF-kappaB activation whereas c-Myc potentiated 12-o-tetracecanyolphorbol-13-acetate (TPA)-induced NF-kappaB activation. Heregulin-mediated NF-kappaB activation correlated with phosphorylation of epidermal growth factor receptor (EGFR) and ErbB3 but not her2/neu. Tryphostin AG1517, which inhibits heregulin-mediated phosphorylation of EGFR, her2/neu and ErbB3 reduced NF-kappaB activation. In contrast, emodin, which blocks phosphorylation of her2/neu by heregulin, failed to reduce NF-kappaB activation. These results suggest that heregulin induces NF-kappaB independent of her2/neu. PI3 kinase/AKT, protein kinase A (PKA) and IkappaB kinase appear to be downstream signaling molecules involved in NF-kappaB activation as specific inhibitors of these kinases but not inhibitors of ERK/MAP kinase or protein kinase C reduced heregulin-mediated NF-kappaB activation. Based on these results, we propose that heregulin increases the expression of pro-invasive, pro-metastatic and anti-apoptotic genes in cancer cells through autocrine activation of NF-kappaB, which leads to invasive and drug-resistant growth of breast cancer.
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PMID:Identification of signal transduction pathways involved in constitutive NF-kappaB activation in breast cancer cells. 1196 Mar 79

The Her-2/neu oncogene, the second member of the epidermal growth factor (EGF) receptor family, encodes a transmembrane tyrosine kinase receptor. Overexpression of Her-2/neu in approximately 30% of breast cancers is associated with poor overall survival. Recently, we have found that Her-2/neu activates nuclear factor (NF)-kappaB via a phosphatidylinositol 3 kinase (PI3-K)-Akt kinase signaling pathway in mouse mammary tumor virus (MMTV)-Her-2/neu NF639 mouse breast cancer cells. Surprisingly, the IkappaB kinase (IKK) kinase complex, implicated in proteasome-mediated degradation of IkappaB-alpha and activation of NF-kappaB via the canonical pathway, was not activated in these cells. Degradation of IkappaB-alpha was mediated via calpain, which in B cells is facilitated by phosphorylation of IkappaB-alpha by the protein kinase CK2. Here, we report that the inhibition of CK2 blocks Her-2/neu-mediated activation of NF-kappaB. NF639 breast cancer cells, stably expressing CK2alpha or CK2alpha' kinase-inactive mutants, displayed decreased NF-kappaB binding and reduced ability to grow in soft agar, as well as increased sensitivity to tumor necrosis factor (TNF)-alpha killing. Similarly, CK2 kinase-inactive subunits inhibited NF-kappaB activity in Hs578T human breast cancer cells, which also display elevated CK2 activity. In NIH 3T3 fibroblasts, which express low basal NF-kappaB and CK2 activities, overexpression of CK2 by retroviral gene delivery led to increased IkappaB-alpha turnover and the induction of classical NF-kappaB (p50/RelA). Thus, CK2 plays an important role in Her-2/neu signaling, promoting IkappaB-alpha degradation and, thereby, NF-kappaB activation. Furthermore, because ectopic CK2 activity appears sufficient to induce NF-kappaB, the elevated CK2 activity observed in many primary human breast cancers likely plays a role in aberrant activation of NF-kappaB and, therefore, represents a potential therapeutic target.
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PMID:Protein kinase CK2 promotes aberrant activation of nuclear factor-kappaB, transformed phenotype, and survival of breast cancer cells. 1243 79

Constitutively active HER2/neu activates nuclear factor kappa-B (NF-kappaB) in cells and induces their resistance to apoptotic stimuli such as tumor necrosis factor-alpha (TNF-alpha). Here, we show that integrin-linked kinase (ILK), the crucial signal transducer in the integrin pathway, is involved in HER2/neu-mediated activation of NF-kappaB. Expression of HER2/neu increases ILK activity. Blocking ILK activity with a kinase-deficient mutant ILK (ILK-KD) inhibits NF-kappaB activation and sensitizes HER2/neu-transformed cells to TNF-alpha-induced apoptosis. Stable expression of ILK-KD in HER2/neu-transformed cells suppressed Akt phosphorylation and the expression of IkappaB kinase alpha and beta (IKKalpha and beta) at both the protein and mRNA levels, preventing IkappaB-alpha degradation and NF-kappaB activation. Furthermore, HER2/neu stimulated the transcriptional activity of the putative IKKbeta promoter through ILK and Akt. Our results demonstrate that upregulation of IKKalpha and IKKbeta by the ILK/Akt pathway is required for the HER2/neu-mediated NF-kappaB antiapoptotic pathway.
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PMID:Upregulation of IKKalpha/IKKbeta by integrin-linked kinase is required for HER2/neu-induced NF-kappaB antiapoptotic pathway. 1502 10

NF-kappaB is constitutively active in many solid tumors, including breast cancer. However, the role of NF-kappaB in breast carcinogenesis is unknown. Ikkalpha(AA/AA) "knockin" mice in which activation of IkappaB kinase alpha (IKKalpha) is prevented by replacement of activation loop serines with alanines exhibit delayed mammary gland growth during pregnancy, because IKKalpha activity is required for cyclin D1 induction and proliferation of lobuloalveolar epithelial cells. Given the role of cyclin D1 in breast and mammary cancer, we examined involvement of IKKalpha in mammary carcinogenesis induced by oncogenes or a chemical carcinogen, 7,12-dimethylbenz[a]anthracene (DMBA). The Ikkalpha(AA) mutation retarded tumor development in response to either 7,12-dimethylbenzaanthracene or the MMTV-c-neu (ErbB2/Her2) transgene but had no effect on MMTV-v-Ha-ras-induced cancer, although both oncogenes rely on cyclin D1. Strikingly, primary Ikkalpha(AA/AA)/MMTV-c-neu carcinoma cells exhibited diminished self-renewal capacity, resulting in the inability to establish secondary tumors. Ikkalpha(AA/AA)/MMTV-c-neu carcinoma cells underwent premature senescence when cultured under conditions used for propagation of mammary gland stem cells. Thus, IKKalpha is not only a regulator of mammary epithelial proliferation, but is also an important contributor to ErbB2-induced oncogenesis, providing signals that maintain mammary tumor-initiating cells. IKKalpha may represent a novel and specific target for treatment of ErbB2-positive breast cancer.
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PMID:IkappaB kinase alpha kinase activity is required for self-renewal of ErbB2/Her2-transformed mammary tumor-initiating cells. 1789 Mar 19