The DEK oncogene promotes cellular proliferation through paracrine Wnt signaling in Ron receptor-positive breast cancers.
The DEK oncogene promotes cellular proliferation through paracrine Wnt signaling in Ron receptor-positive breast cancers.
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作者：
Disease progression and recurrence are major barriers to surviving breast cancer. Understanding the etiology of recurrent or metastatic breast cancer and underlying mechanisms is critical for the development of new treatments and improved survival. Here, we report that two commonly over-expressed breast cancer oncogenes, Ron and DEK, cooperate to promote advanced disease through multi-pronged effects on β-catenin signaling. The Ron receptor is commonly activated in breast cancers, and Ron over-expression in human disease stimulates β-catenin nuclear translocation and is an independent predictor of metastatic dissemination. Dek is a chromatin-associated oncogene whose expression has been linked to cancer through multiple mechanisms, including β-catenin activity. We demonstrate here that Dek is a downstream target of Ron receptor activation in murine and human models. The absence of Dek in the MMTV-Ron mouse model led to a significant delay in tumor development, characterized by decreased cell proliferation, diminished metastasis, and fewer cells expressing cancer stem cell markers. Dek complementation of cell lines established from this model was sufficient to promote cellular growth and invasion in vitro and in vivo. Mechanistically, Dek expression stimulated the production and secretion of Wnt ligands to sustain an autocrine/paracrine canonical β-catenin signaling loop. Finally, we show that Dek over-expression promotes tumorigenic phenotypes in immortalized human mammary epithelial MCF10A cells and, in the context of Ron receptor activation, correlates with disease recurrence and metastasis in patients. Overall, our studies demonstrate that DEK over-expression, due in part to Ron receptor activation, drives breast cancer progression through the induction of Wnt/β-catenin signaling.
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影响因子：
14.9
作者：
Kavanaugh GM;Wise-Draper TM;Morreale RJ;Morrison MA;Gole B;Schwemberger S;Tichy ED;Lu L;Babcock GF;Wells JM;Drissi R;Bissler JJ;Stambrook PJ;Andreassen PR;Wiesmüller L;Wells SI
通讯作者：
Wells SI
影响因子：
2.4
作者：
Krol, M.;Polanska, J.;Motyl, T.
通讯作者：
Motyl, T.
影响因子：
8
作者：
Lane, TF;Philip, L
通讯作者：
Philip, L
影响因子：
4.8
作者：
Debnath, J;Muthuswamy, SK;Brugge, JS
通讯作者：
Brugge, JS
DOI：
10.2217/14796694.3.4.441
发表时间：
2007-08-01
期刊：
Future oncology (London, England)
影响因子：
--
作者：
Leonis, Mike A;Thobe, Megan N;Waltz, Susan E
通讯作者：
Waltz, Susan E