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.

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    • "According to its positive regulation of apoptosis, a substantial body of evidence implicates JNK proteins in tumor suppression (Davis, 2000; Wagner and Nebreda, 2009). First, animal studies have demonstrated that JNK1-deficient mice are highly susceptible to tumor development (She et al., 2002; Tong et al., 2007), and more recently, impaired JNK signaling was shown to accelerate tumorigenesis in prostate, breast, or pancreatic cancer (Cellurale et al., 2012; Davies et al., 2014; Hü bner et al., 2012). Second, JNK can sensitize cancer cells to genotoxic stress-induced cell death (Sau et al., 2012; Song et al., 2012; Xiao et al., 2012), and knockdown of both JNK1 and JNK2 by small interfering RNA impaired apoptosis in response to anticancer drugs (Oleinik et al., 2007). "
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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.
    Full-text · Article · Nov 2014 · Chemistry & biology
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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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    ABSTRACT: Background Peroxisome proliferator-activated receptors gamma (PPARγ) ligands have been shown to inhibit the growth of non-small cell lung cancer (NSCLC) cells. However, the mechanisms underlying this effect remain incompletely elucidated. Methods Cell proliferation and apoptosis were measured by cell viability, MTT and caspase3/7 activity assays. Phosphorylation/protein expression and gene silence/overexpression of AMPKα, phosphoinositide-dependent protein kinase 1 (PDK1), Egr-1 and PPARγ were performed by Western blot and siRNA/transfection assays. Dual-Luciferase Reporter Kit was used to measure the PPAR response elements (PPRE) reporter and PDK1 promoter activities, and ChIP assay was used to detect the Egr-1 protein binding to the DNA site in the PDK1 gene promoter. Results We found that ciglitazone, one synthetic PPARγ ligand, inhibited growth and induced apoptosis of NSCLC cells through decreased expression of PDK1, which was not blocked by GW9662 (a specific PPARγ antagonist). Overexpression of PDK1 overcame the effect of ciglitazone on cell growth and caspase 3/7 activity. Ciglitazone increased the phosphorylation of AMPKα and c-Jun N-terminal kinase (JNK), and the inhibitor of AMPK (compound C), but not JNK (SP600125), reversed the effect of ciglitazone on PDK1 protein expression. Ciglitazone reduced PDK1 gene promoter activity, which was not observed in cells exposed to compound C, but not silenced of PPARγ siRNA. Combination of ciglitazone and metformin further reduced PDK1 expression and promoter activity. Furthermore, we showed that ciglitazone induced the protein expression of Egr-1, which was not observed in cells silencing of AMPKα. Moreover, silencing of Egr-1 abrogated the effect of ciglitazone on PDK1 promoter activity and cell growth. On the contrary, overexpression of Egr-1 enhanced the effect of ciglitazone on PDK1 gene promoter activity. ChIP assays demonstrated that ciglitazone induced Egr-1 protein bind to the specific DNA site in the PDK1 gene promoter. Conclusion Collectively, our results demonstrate that ciglitazone inhibits PDK1 expression through AMPKα-mediated induction of Egr-1 and Egr-1 binding to the specific DNA site in the PDK1 gene promoter, which is independent of PPARγ. Activation of AMPKα by metformin enhances the effect of ciglitazone. In turn, this leads to inhibition of NSCLC cell proliferation.
    Full-text · Article · Jun 2014 · Molecular Cancer
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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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    ABSTRACT: Tumor progression is coincident with mechanochemical changes in the extracellular matrix (ECM). We hypothesized that tumor stroma stiffening, alongside a shift in the ECM composition from a basement membrane-like microenvironment toward a dense network of collagen-rich fibers during tumorigenesis, confers resistance to otherwise powerful chemotherapeutics. To test this hypothesis, we created a high-throughput drug screening platform based on our poly(ethylene glycol)-phosphorylcholine (PEG-PC) hydrogel system, and customized it to capture the stiffness and integrin-binding profile of in vivo tumors. We report that the efficacy of a Raf kinase inhibitor, sorafenib, is reduced on stiff, collagen-rich microenvironments, independent of ROCK activity. Instead, sustained activation of JNK mediated this resistance, and combining a JNK inhibitor with sorafenib eliminated stiffness-mediated resistance in triple negative breast cancer cells. Surprisingly, neither ERK nor p38 appears to mediate sorafenib resistance, and instead, either ERK or p38 inhibition rescued sorafenib resistance during JNK inhibition, suggesting negative crosstalk between these signaling pathways on stiff, collagen-rich environments. Overall, we discovered that β1 integrin and its downstream effector JNK mediate sorafenib resistance during tumor stiffening. These results also highlight the need for more advanced cell culture platforms, such as our high-throughput PEG-PC system, with which to screen chemotherapeutics.
    Full-text · Article · Apr 2014 · Biomaterials
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