Co-opted JNK/SAPK Signaling in Wnt/β-catenin–Induced Tumorigenesis
نویسندگان
چکیده
Aberrant stimulation of the canonical Wnt pathway induces mammary tumorigenesis in mice. It has been well documented that two types of tumors, adenocarcinoma and adenocarcinoma with squamous metaplasia, develop in these mutants. However, the molecular mechanism underlying the induction of squamous transdifferentiation remains largely unknown. Here, we show that JNK/SAPK signaling plays an important role in Wnt-dependent mammary development and malignant transformation. The JNK/SAPK pathway is stimulated in pregnancy-mediated lobulo-alveolar morphogenesis, a process highly dependent on Wnt/β-catenin signaling. Strong elevations of JNK/SAPK signaling are associated with squamous metaplasia of the Wnt-induced adenocarcinoma. Reconstitution of β-catenin and JNK/SAPK signaling activities also promotes expression of the squamous cell marker in cultured epithelial cells. Furthermore, a synergistic activation of these two pathways can be identified in the malignant squamous cells of human endometrial and lung cancers. This is potentially a significant discovery in modern cancer therapy because of the effectiveness of an angiogenesis inhibitor, Avastin, for the treatment of adenocarcinoma, but not squamous cell carcinoma, in human lung cancers. Our finding may improve the usage of biomarkers to distinguish these two poorly differentiated tumor types, sharing similar histologic features. Neoplasia (2008) 10, 1004–1013 Introduction Wnt signaling is important for diverse processes during embryonic, fetal, and postnatal development [1]. Deregulation of Wnt signaling has also been linked to pathogenesis of various diseases [2]. β-Catenin, a key component of adherens junction, plays an essential role in transduction of the canonical Wnt pathway [3]. The cellular level of βcatenin is controlled by a disruption complex, including Axin, APC, and GSK-3β [4]. In the absence of a Wnt signal, this complex binds to β-catenin, mediating its phosphorylation and degradation through the ubiquitin-mediated proteolysis system [5]. Wnt signals perturb the formation of the disruption complex by activating the upstream regulators, leading to nuclear accumulations of β-catenin [6]. The downstream signaling events are triggered by its interaction with transcription factors of the lymphoid enhancer factor/T cell factor (LEF/ TCF) family to regulate target gene expression [7]. Wnt signaling is intimately involved in the development and neoplastic transformation of the mammary gland [8]. Several members of the Wnt family are expressed in the epithelium and stromal Address all correspondence to: Wei Hsu, 601 Elmwood Avenue, BOX 611, Rochester, NY 14642. E-mail: [email protected] This work was supported by National Institutes of Health grant CA106308 to W.H. Received 7 May 2008; Revised 19 June 2008; Accepted 23 June 2008 Copyright © 2008 Neoplasia Press, Inc. All rights reserved 1522-8002/08/$25.00 DOI 10.1593/neo.08548 www.neoplasia.com Volume 10 Number 9 September 2008 pp. 1004–1013 1004
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