Role of JNK in Mammary Gland Development and Breast Cancer

Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Cancer Research (Impact Factor: 9.33). 11/2011; 72(2):472-81. DOI: 10.1158/0008-5472.CAN-11-1628
Source: PubMed


cJun NH(2)-terminal kinase (JNK) signaling has been implicated in the developmental morphogenesis of epithelial organs. In this study, we employed a compound deletion of the murine Jnk1 and Jnk2 genes in the mammary gland to evaluate the requirement for these ubiquitously expressed genes in breast development and tumorigenesis. JNK1/2 was not required for breast epithelial cell proliferation or motility. However, JNK1/2 deficiency caused increased branching morphogenesis and defects in the clearance of lumenal epithelial cells. In the setting of breast cancer development, JNK1/2 deficiency significantly increased tumor formation. Together, these findings established that JNK signaling is required for normal mammary gland development and that it has a suppressive role in mammary tumorigenesis.


Available from: Julie Cavanagh Kyros, Nov 12, 2015

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Article: Role of JNK in Mammary Gland Development and Breast Cancer

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    ABSTRACT: The c-Jun N-terminal kinase (JNK) family, with its three members JNK1, JNK2, and JNK3, is a subfamily of mitogen-activated protein kinases. Involved in many aspects of cellular processes, JNK has been also associated with pathological states such as neurodegenerative diseases, inflammation, and cancers. In oncology, each isoform plays a distinct role depending on the context of the targeted tissue/organ, the tumor stage, and, most likely, the signaling pathway activated upstream. Consequently, the current challenge in finding new successful anti-JNK therapies is to design isoform-selective inhibitors of the JNKs. In this review, a particular focus is given to the JNK inhibitors that have been developed thus far when examining 3D structures of various JNK-inhibitor complexes. Using current data regarding structure-activity relationships and medicinal chemistry approaches, our objective is to provide a better understanding of the design and development of selective JNK inhibitors in the present and future. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Chemistry & biology 11/2014; 21(11):1433-1443. DOI:10.1016/j.chembiol.2014.09.007 · 6.65 Impact Factor
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    • "Stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) is a mitogen-activated protein kinase family member that is activated by diverse stimuli and plays a critical role in regulating cell fate, being implicated in a multitude of diseases ranging from cancer to neurological, immunological and inflammatory conditions. JNK signaling is required for normal mammary gland development and has a suppressive role in mammary tumorigenesis [8]. AMP-activated protein kinase (AMPK), a heterotrimeric protein complex with serine/threonine kinase activity, has been involved in the regulation of a number of physiological processes including β-oxidation of fatty acids, lipogenesis, protein and cholesterol synthesis, as well as cell cycle inhibition and apoptosis. "
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    • "4,5). Activation of JNK has been reported to mediate either pro-apoptotic or anti-apoptotic signaling pathways depending on stimuli [50] [51], with parallel contradictory roles in vivo, either supporting tumor growth [52- 55] or suppressing tumorigenesis [56] [57] [58] [59]. Our results indicate a role for JNK in enhancing cell survival during sorafenib treatment, and for the first time we show that JNK activation is regulated by substrate stiffness. "
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    Biomaterials 04/2014; 35(22). DOI:10.1016/j.biomaterials.2014.03.058 · 8.56 Impact Factor
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