Recent studies have shown that Cox 2 mRNA and protein expression in several cancer cell lines are regu lated by the insulin like growth factor 1R/PI3K and nuclear factor kappa B/nuclear selleck chemicals Gefitinib factor of kappa selleck chem light polypeptide gene enhancer in B cells inhibitor pathways. In addition Inhibitors,Modulators,Libraries thenthereby to the PI3K/Akt Inhibitors,Modulators,Libraries pathway, the Ras/ Inhibitors,Modulators,Libraries Raf/MAPK pathway is also a downstream transducer of IGF 1R signaling. Inhibitors,Modulators,Libraries The IGF 1R signaling pathway Inhibitors,Modulators,Libraries plays a major role in cell proliferation, apoptosis, invasion, and angiogenesis. Moreover, IGF 1R has been shown to upregulate Cox 2 mRNA expression and PGE2 synthesis in cancer cells.

Although we found that IGF 1R expression was neither increased nor constitutively acti vated in MCF 7/DOX cells, activation of the IGF 1R pathway may still contribute to Cox 2 expression and our efforts are ongoing to determine any further possibility.

Treating cells with EGF Inhibitors,Modulators,Libraries also increased pAkt and pERK1/2 expression in MCF 7/DOX cells. To investi gate the role of the PI3K/Akt pathway in Cox 2 expres sion, we Inhibitors,Modulators,Libraries studied the effect of the Inhibitors,Modulators,Libraries PI3K/Akt Inhibitors,Modulators,Libraries inhibitor LY294002 on EGF induced pAkt and Cox 2 expression. Western blot analysis showed that LY294002 dramati cally suppressed pAkt activation and Cox 2 expression induced by EGF in MCF 7/DOX cells. Because Cox 2 exerts its effects by producing PGE2, which binds to specific EP receptors, we investi gated the role of specific EP receptors in Cox 2 mediated invasion of MCF 7/DOX cells.

PGE2 treatment induced expression of Inhibitors,Modulators,Libraries the EP1 and EP3 receptors, sug gesting that these two receptors are likely involved Inhibitors,Modulators,Libraries in the invasiveness by MCF 7/DOX cells.

Both EP1 and EP3 receptors played an important role in Cox 2 induced invasion of MCF 7/DOX cells. We showed that selective inhibition of EP1 and EP3 using siRNAs inhib ited PGE2 induced invasion of MCF 7/DOX cells, as well as expression of MMP 2 and MMP 9. A previous Inhibitors,Modulators,Libraries study showed increased Cox 2 expression in patients with poorly differentiated breast cancer and poor clinical outcomes for patients treated with doxorubicin. However, the expression Inhibitors,Modulators,Libraries pattern of EP receptors has never been studied in breast cancer.

Therefore, our find ings are the first to suggest a pivotal role for the EP1 and EP3 receptors in doxorubicin resistant breast cancer cells.

Conclusions Together, we have demonstrated that invasiveness of MCF 7/DOX cells results from Cox 2 activation, which is induced by Inhibitors,Modulators,Libraries either the selleck products EGFR activated PI3K/Akt Inhibitors,Modulators,Libraries method or MAPK pathway.

Inhibiting Cox 2 or the EGFR pathway effectively inhibited invasiveness Lapatinib solubility of MCF 7/DOX cells. We also found that the EP receptors EP1 and EP3 are important for Cox 2 induced invasion of MCF 7/DOX cells. Therefore, not only Cox 2 but also EP1 and EP3 could be important targets for chemosensitizing and inhibiting metastasis in chemotherapy resistant breast cancers.