These obser vations indicate that PEA3 subfamily members are likely central regulators in carcinogenesis and are potential therapeutic targets. A unifying view of PEA3 function in cancer is there fore that it is a regulator of MMP expression selleck chemical in response to ERK MAP kinase pathway signaling. How ever, to date few studies have connected these molecular events together in a single system and the potential role of PEA3 subfamily members in oesophageal adenocarci noma has not previously been investigated. Indeed, none of the wider ETS domain transcription factor family has been implicated in oesophageal adenocarcinoma, although Ets 1, Ets 2 and Elk 1 have been shown to be over expressed on squamous oesophageal cancers. Here, we show that high PEA3 expression is a Inhibitors,Modulators,Libraries frequent occurrence in oesophageal adenocarcinoma.

In oesophageal adenocarcinoma cell line models, PEA3 plays a role in promoting invasion and is also important for oesophageal cell proliferation. Molecularly, the inva sive properties Inhibitors,Modulators,Libraries are likely due Inhibitors,Modulators,Libraries to the activation of MMP 1 expression. Furthermore we also show an important role of the ERK pathway in promoting PEA3 activity and ensuing invasion. In adenocarcinoma tissue, the co occurrence of PEA3 family member expression corre lates with enhanced MMP 1 expression. Active ERK signaling correlates with enhanced stage suggesting an important role in promoting metastasis via PEA3 and ER81. These results indicate that the ERK PEA3 MMP 1 axis identified in oesophageal cancer cells is also likely to be operative in oesophageal adenocarcinoma tissue.

This pathway could potentially be targeted by drug inhi bition with a view Inhibitors,Modulators,Libraries to improve prognosis. Results The expression of PEA3 family members in oesophageal tissues To establish whether members of the PEA3 subfamily ETS domain transcription factors might play a role in oesophageal adenocarcinomas, we first determined the expression of PEA3 protein in normal oesophageal tissue and oesophageal adenocarcinomas by construct ing a TMA from 27 samples from normal patients and 58 samples from oesophageal adenocarcinomas, along with samples from adjacent normal tissue. We also included 23 samples from patients with Barretts oeso phagous as this is thought to be a precursor condition to adenocarcinoma development. Samples were then scored as PEA3 positive if they had moderate high PEA3 protein levels.

Very few normal or Barretts samples contained moderate high Inhibitors,Modulators,Libraries PEA3 protein levels but in contrast, over 33% of sam ples from adenocarcinomas exhibited moderate high PEA3 protein levels. Importantly, when we split the adenocarcinomas into T and N stage tumours, the frequency of occurrence of high PEA3 protein levels was significantly higher in the nodal tumours, suggesting an association of PEA3 expression with www.selleckchem.com/products/MLN-2238.html metastasis. In addition to analysing protein levels, we also deter mined the levels of PEA3 mRNA in oesophageal tissue samples alongside the levels of the related subfamily member ER81.