As indicated above, RasG12V alone induced the release of CXCL8 an

As indicated above, RasG12V alone induced the release of CXCL8 and of CCL2. However, unlike CXCL8, CCL2 expression former was reduced when p53 was down regulated in the context of Ras hyper activation. These findings agree with those of recent studies showing that p53 was bound to CCL2 5 UTR and that the knockdown of human p53 has led to strong negative regulation of CCL2 in macro phages. Therefore, combining Ras hyper activation with down regulation of p53 demonstrated the exist ence of different regulatory circuits for CXCL8 as com pared to CCL2. Despite its ability to act alone in the tumor cells, RasG12V had a relatively minor effect Inhibitors,Modulators,Libraries on pro malignancy activities in MCF 7 breast tumor cells, as compared to the in flammatory cytokines.

Actually, it was the joint activity of activated Inhibitors,Modulators,Libraries Ras and Inhibitors,Modulators,Libraries the inflammatory cyto kines that had the most powerful effects on CXCL8 release and metastasis. Our seminal finding in this re spect is that activities similar to those of RasG12V were achieved using WT Ras following its activation by TNF. The strong metastasizing activities resulting Inhibitors,Modulators,Libraries out of the cooperation between hyper activated Ras and TNF suggest that the activation of WT Ras by TNF may give rise to more aggressive disease in breast cancer patients expressing WT Ras and high levels of TNF. Conclusions In this study we have shown that TNF rescued the tumor promoting potential of WT Ras and have demon strated cooperativity between TNF and activated Ras in metastasis. The mechanisms revealed in this study and in other supporting investigations suggest that oncogenic events are promoted by inflammatory signals that reside at the tumor microenvironment of breast tumors.

Addi tional research in other breast tumor systems should be taken in order to substantiate these mechanisms, as they may have a significant impact on therapeutic approaches for the treatment of cases of breast cancer in which the tumors express high levels of TNF and Ras is Inhibitors,Modulators,Libraries generally not mutated. In light of such mechanisms, we may need to consider the use of inhibitors of mutated Ras in patients who do not have any apparent constitutive activation of the oncogene due to its muta tion and also express high levels of TNF, as is the case for many breast cancer patients. Such inhibitors may in clude the farnesyl transferase inhibitors that are cur rently in clinical trials.

Furthermore, the interaction observed between TNF and WT Ras suggests that the therapeutic potential of Ras inhibitors would be en hanced if they were to be used together with the clinic ally nearly available TNF inhibitors, which have already been investigated in the context of several other types of ma lignancies and have proven to be safe. Thus, the novel findings presented in our study have great clinical relevance, as they emphasize the need to consider the use of new therapeutic approaches in the treatment of breast cancer.

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