The DEK oncogene promotes cellular proliferation through paracrine Wnt signaling in Ron receptor-positive breast cancers.

Disease progression and recurrence are major barriers to survival for breast cancer patients. 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 overexpressed breast cancer oncogenes, Ron (Recepteur d'Origine Nantaise) and DEK, cooperate to promote advanced disease through multipronged effects on ß-catenin signaling. The Ron receptor is commonly activated in breast cancers, and Ron overexpression in human disease stimulates ß-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 ß-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 mammary cancer stem cell markers. Dek complementation of cell lines established from this model was sufficient to promote cellular growth and invasion. Mechanistically, Dek expression stimulated the production and secretion of Wnt ligands to sustain an autocrine/paracrine canonical ß-catenin signaling loop. Finally, we show that Dek overexpression 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 overexpression, due in part to Ron receptor activation, drives breast cancer progression through the induction of Wnt/ß-catenin signaling.

Tumour necrosis factor alpha blockade induces an anti-inflammatory growth hormone signalling pathway in experimental colitis.

BACKGROUND: Neutralisation of tumour necrosis factor alpha (TNFalpha) restores systemic growth hormone function in patients with Crohn's disease, and induces mucosal healing. Anabolic effects of growth hormone depend on activation of the STAT5 transcription factor. Although it has recently been reported that both administration of growth hormone and neutralisation of TNFalpha reduce mucosal inflammation in experimental colitis, whether this involved activation of STAT5 in the gut is not known. AIM: To determine whether TNFalpha blockade in colitis up regulates a growth hormone:STAT5 signalling pathway in the colon. METHODS: Interleukin 10-deficient mice and wild-type controls received growth hormone or anti-TNFalpha antibody, and T84 human colon carcinoma cells were treated with TNFalpha or growth hormone. Activation and expression of STAT5b, peroxisome proliferator-activated receptor gamma (PPARgamma), NFkappaB/IkappaB and growth hormone receptor were determined. RESULTS: Growth hormone activated STAT5b and up regulated expression of PPARgamma in normal mouse colon; inflamed colon was partially resistant to this. Chronic administration of growth hormone, nevertheless, significantly reduced activation of colonic NFkappaB (p = 0.028). Neutralisation of TNFalpha rapidly increased abundance of growth hormone receptor, activation of STAT5 and abundance of PPARgamma in the colon, but reduced activation of NFkappaB in colitis. Growth hormone activated STAT5, and directly reduced TNFalpha activation of NFkappaB, in T84 cells. CONCLUSIONS: Reduced activation of colonic STAT5 and expression of PPARgamma may contribute to persistent mucosal inflammation in colitis. Up regulation of STAT5 and PPARgamma, either through neutralisation of TNFalpha or chronic administration of growth hormone, may exert an anti-inflammatory effect in inflammatory bowel disease.