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IκB kinase α kinase activity is required for self-renewal of ErbB2/Her2-transformed mammary tumor-initiating cells

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Zeitschriftentitel: Proceedings of the National Academy of Sciences
Personen und Körperschaften: Cao, Yixue, Luo, Jun-li, Karin, Michael
In: Proceedings of the National Academy of Sciences, 104, 2007, 40, S. 15852-15857
Format: E-Article
Sprache: Englisch
veröffentlicht:
Proceedings of the National Academy of Sciences
Schlagwörter:
Multidisciplinary
author_facet Cao, Yixue
Luo, Jun-li
Karin, Michael
Cao, Yixue
Luo, Jun-li
Karin, Michael
author Cao, Yixue
Luo, Jun-li
Karin, Michael
spellingShingle Cao, Yixue
Luo, Jun-li
Karin, Michael
Proceedings of the National Academy of Sciences
IκB kinase α kinase activity is required for self-renewal of ErbB2/Her2-transformed mammary tumor-initiating cells
Multidisciplinary
author_sort cao, yixue
spelling Cao, Yixue Luo, Jun-li Karin, Michael 0027-8424 1091-6490 Proceedings of the National Academy of Sciences Multidisciplinary http://dx.doi.org/10.1073/pnas.0706728104 <jats:p> NF-κB is constitutively active in many solid tumors, including breast cancer. However, the role of NF-κB in breast carcinogenesis is unknown. <jats:italic>Ikk</jats:italic> α <jats:sup> <jats:italic>AA</jats:italic> / <jats:italic>AA</jats:italic> </jats:sup> “knockin” mice in which activation of IκB kinase α (IKKα) is prevented by replacement of activation loop serines with alanines exhibit delayed mammary gland growth during pregnancy, because IKKα 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 IKKα in mammary carcinogenesis induced by oncogenes or a chemical carcinogen, 7,12-dimethylbenz[ <jats:italic>a</jats:italic> ]anthracene (DMBA). The <jats:italic>Ikk</jats:italic> α <jats:sup> <jats:italic>AA</jats:italic> </jats:sup> mutation retarded tumor development in response to either 7,12-dimethylbenzaanthracene or the <jats:italic>MMTV-c-neu</jats:italic> ( <jats:italic>ErbB2</jats:italic> / <jats:italic>Her2</jats:italic> ) transgene but had no effect on <jats:italic>MMTV-v-Ha-ras</jats:italic> -induced cancer, although both oncogenes rely on cyclin D1. Strikingly, primary <jats:italic>Ikk</jats:italic> α <jats:sup> <jats:italic>AA</jats:italic> / <jats:italic>AA</jats:italic> </jats:sup> / <jats:italic>MMTV-c-neu</jats:italic> carcinoma cells exhibited diminished self-renewal capacity, resulting in the inability to establish secondary tumors. <jats:italic>Ikk</jats:italic> α <jats:sup> <jats:italic>AA</jats:italic> / <jats:italic>AA</jats:italic> </jats:sup> / <jats:italic>MMTV-c-neu</jats:italic> carcinoma cells underwent premature senescence when cultured under conditions used for propagation of mammary gland stem cells. Thus, IKKα 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. IKKα may represent a novel and specific target for treatment of ErbB2-positive breast cancer. </jats:p> IκB kinase α kinase activity is required for self-renewal of ErbB2/Her2-transformed mammary tumor-initiating cells Proceedings of the National Academy of Sciences
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title IκB kinase α kinase activity is required for self-renewal of ErbB2/Her2-transformed mammary tumor-initiating cells
title_unstemmed IκB kinase α kinase activity is required for self-renewal of ErbB2/Her2-transformed mammary tumor-initiating cells
title_full IκB kinase α kinase activity is required for self-renewal of ErbB2/Her2-transformed mammary tumor-initiating cells
title_fullStr IκB kinase α kinase activity is required for self-renewal of ErbB2/Her2-transformed mammary tumor-initiating cells
title_full_unstemmed IκB kinase α kinase activity is required for self-renewal of ErbB2/Her2-transformed mammary tumor-initiating cells
title_short IκB kinase α kinase activity is required for self-renewal of ErbB2/Her2-transformed mammary tumor-initiating cells
title_sort iκb kinase α kinase activity is required for self-renewal of erbb2/her2-transformed mammary tumor-initiating cells
topic Multidisciplinary
url http://dx.doi.org/10.1073/pnas.0706728104
publishDate 2007
physical 15852-15857
description <jats:p> NF-κB is constitutively active in many solid tumors, including breast cancer. However, the role of NF-κB in breast carcinogenesis is unknown. <jats:italic>Ikk</jats:italic> α <jats:sup> <jats:italic>AA</jats:italic> / <jats:italic>AA</jats:italic> </jats:sup> “knockin” mice in which activation of IκB kinase α (IKKα) is prevented by replacement of activation loop serines with alanines exhibit delayed mammary gland growth during pregnancy, because IKKα 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 IKKα in mammary carcinogenesis induced by oncogenes or a chemical carcinogen, 7,12-dimethylbenz[ <jats:italic>a</jats:italic> ]anthracene (DMBA). The <jats:italic>Ikk</jats:italic> α <jats:sup> <jats:italic>AA</jats:italic> </jats:sup> mutation retarded tumor development in response to either 7,12-dimethylbenzaanthracene or the <jats:italic>MMTV-c-neu</jats:italic> ( <jats:italic>ErbB2</jats:italic> / <jats:italic>Her2</jats:italic> ) transgene but had no effect on <jats:italic>MMTV-v-Ha-ras</jats:italic> -induced cancer, although both oncogenes rely on cyclin D1. Strikingly, primary <jats:italic>Ikk</jats:italic> α <jats:sup> <jats:italic>AA</jats:italic> / <jats:italic>AA</jats:italic> </jats:sup> / <jats:italic>MMTV-c-neu</jats:italic> carcinoma cells exhibited diminished self-renewal capacity, resulting in the inability to establish secondary tumors. <jats:italic>Ikk</jats:italic> α <jats:sup> <jats:italic>AA</jats:italic> / <jats:italic>AA</jats:italic> </jats:sup> / <jats:italic>MMTV-c-neu</jats:italic> carcinoma cells underwent premature senescence when cultured under conditions used for propagation of mammary gland stem cells. Thus, IKKα 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. IKKα may represent a novel and specific target for treatment of ErbB2-positive breast cancer. </jats:p>
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author Cao, Yixue, Luo, Jun-li, Karin, Michael
author_facet Cao, Yixue, Luo, Jun-li, Karin, Michael, Cao, Yixue, Luo, Jun-li, Karin, Michael
author_sort cao, yixue
container_issue 40
container_start_page 15852
container_title Proceedings of the National Academy of Sciences
container_volume 104
description <jats:p> NF-κB is constitutively active in many solid tumors, including breast cancer. However, the role of NF-κB in breast carcinogenesis is unknown. <jats:italic>Ikk</jats:italic> α <jats:sup> <jats:italic>AA</jats:italic> / <jats:italic>AA</jats:italic> </jats:sup> “knockin” mice in which activation of IκB kinase α (IKKα) is prevented by replacement of activation loop serines with alanines exhibit delayed mammary gland growth during pregnancy, because IKKα 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 IKKα in mammary carcinogenesis induced by oncogenes or a chemical carcinogen, 7,12-dimethylbenz[ <jats:italic>a</jats:italic> ]anthracene (DMBA). The <jats:italic>Ikk</jats:italic> α <jats:sup> <jats:italic>AA</jats:italic> </jats:sup> mutation retarded tumor development in response to either 7,12-dimethylbenzaanthracene or the <jats:italic>MMTV-c-neu</jats:italic> ( <jats:italic>ErbB2</jats:italic> / <jats:italic>Her2</jats:italic> ) transgene but had no effect on <jats:italic>MMTV-v-Ha-ras</jats:italic> -induced cancer, although both oncogenes rely on cyclin D1. Strikingly, primary <jats:italic>Ikk</jats:italic> α <jats:sup> <jats:italic>AA</jats:italic> / <jats:italic>AA</jats:italic> </jats:sup> / <jats:italic>MMTV-c-neu</jats:italic> carcinoma cells exhibited diminished self-renewal capacity, resulting in the inability to establish secondary tumors. <jats:italic>Ikk</jats:italic> α <jats:sup> <jats:italic>AA</jats:italic> / <jats:italic>AA</jats:italic> </jats:sup> / <jats:italic>MMTV-c-neu</jats:italic> carcinoma cells underwent premature senescence when cultured under conditions used for propagation of mammary gland stem cells. Thus, IKKα 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. IKKα may represent a novel and specific target for treatment of ErbB2-positive breast cancer. </jats:p>
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spelling Cao, Yixue Luo, Jun-li Karin, Michael 0027-8424 1091-6490 Proceedings of the National Academy of Sciences Multidisciplinary http://dx.doi.org/10.1073/pnas.0706728104 <jats:p> NF-κB is constitutively active in many solid tumors, including breast cancer. However, the role of NF-κB in breast carcinogenesis is unknown. <jats:italic>Ikk</jats:italic> α <jats:sup> <jats:italic>AA</jats:italic> / <jats:italic>AA</jats:italic> </jats:sup> “knockin” mice in which activation of IκB kinase α (IKKα) is prevented by replacement of activation loop serines with alanines exhibit delayed mammary gland growth during pregnancy, because IKKα 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 IKKα in mammary carcinogenesis induced by oncogenes or a chemical carcinogen, 7,12-dimethylbenz[ <jats:italic>a</jats:italic> ]anthracene (DMBA). The <jats:italic>Ikk</jats:italic> α <jats:sup> <jats:italic>AA</jats:italic> </jats:sup> mutation retarded tumor development in response to either 7,12-dimethylbenzaanthracene or the <jats:italic>MMTV-c-neu</jats:italic> ( <jats:italic>ErbB2</jats:italic> / <jats:italic>Her2</jats:italic> ) transgene but had no effect on <jats:italic>MMTV-v-Ha-ras</jats:italic> -induced cancer, although both oncogenes rely on cyclin D1. Strikingly, primary <jats:italic>Ikk</jats:italic> α <jats:sup> <jats:italic>AA</jats:italic> / <jats:italic>AA</jats:italic> </jats:sup> / <jats:italic>MMTV-c-neu</jats:italic> carcinoma cells exhibited diminished self-renewal capacity, resulting in the inability to establish secondary tumors. <jats:italic>Ikk</jats:italic> α <jats:sup> <jats:italic>AA</jats:italic> / <jats:italic>AA</jats:italic> </jats:sup> / <jats:italic>MMTV-c-neu</jats:italic> carcinoma cells underwent premature senescence when cultured under conditions used for propagation of mammary gland stem cells. Thus, IKKα 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. IKKα may represent a novel and specific target for treatment of ErbB2-positive breast cancer. </jats:p> IκB kinase α kinase activity is required for self-renewal of ErbB2/Her2-transformed mammary tumor-initiating cells Proceedings of the National Academy of Sciences
spellingShingle Cao, Yixue, Luo, Jun-li, Karin, Michael, Proceedings of the National Academy of Sciences, IκB kinase α kinase activity is required for self-renewal of ErbB2/Her2-transformed mammary tumor-initiating cells, Multidisciplinary
title IκB kinase α kinase activity is required for self-renewal of ErbB2/Her2-transformed mammary tumor-initiating cells
title_full IκB kinase α kinase activity is required for self-renewal of ErbB2/Her2-transformed mammary tumor-initiating cells
title_fullStr IκB kinase α kinase activity is required for self-renewal of ErbB2/Her2-transformed mammary tumor-initiating cells
title_full_unstemmed IκB kinase α kinase activity is required for self-renewal of ErbB2/Her2-transformed mammary tumor-initiating cells
title_short IκB kinase α kinase activity is required for self-renewal of ErbB2/Her2-transformed mammary tumor-initiating cells
title_sort iκb kinase α kinase activity is required for self-renewal of erbb2/her2-transformed mammary tumor-initiating cells
title_unstemmed IκB kinase α kinase activity is required for self-renewal of ErbB2/Her2-transformed mammary tumor-initiating cells
topic Multidisciplinary
url http://dx.doi.org/10.1073/pnas.0706728104