Elevated levels of GTP Rac1 have been shown to cor relate with tumor metastasis and vascular endothelial selleck chemicals llc growth factor expression. Despite the im portance of the upstream signaling mechanisms that facilitate Rac activation, the identity of these mecha nisms in ICC remains unknown. In the present study, we demonstrated for the first time that the protein level of Notch1 is elevated in ICC tissues and that Notch1 over expression promotes migration and Rac1 activation in human ICC 9810 cells. By examining cell morphology and immunofluorescence, we found that Notch1 over expression results in morphological changes and alterations in the F actin cytoskeleton in ICC 9810 cells. These results suggest that upregulation of Notch1 could promote ICC cell migration and inva sion through Rac1 activation.

In the present study, Rac1 inhibition attenuated the effects of secretase on Notch1, resulting in decreased production of the Notch1 intracellular domain and a slight decrease in the shedding of the ectodomain form of Notch1. We have shown that down regulation of Notch1 results in a dramatic decrease in Rac1 activity, suggesting that a mechanism exists to determine whether Rac1 or Notch1 is the preferred substrate for secretase, however, this mechanism requires further elucidation. Conclusions In conclusion, we have shown here that Notch1 ex pression is upregulated in clinical ICC specimens and promotes tumor migration, indicating that Notch1 may be involved in ICC carcinogenesis and progres sion.

These findings suggest that Notch1 could serve as a novel diagnostic and therapeutic target in patients with ICC and thereby establish the potential for targeting Notch signaling as an approach to inhibit tumor metastasis. Background The Her recep tor tyrosine kinases comprise four homologous proteins, which are differentially expressed dur ing development and functional maintenance of the nor mal mammary gland. Spatiotemporally regulated RTK expression, however, is commonly disturbed in neoplastic mammary epithelium. 15% 25% of breast cancers show Her2 receptor overexpression, which has a negative prognostic impact on the outcome of disease. Specific Her2 receptor targeting with antibodies or small molecule kinase inhibitors, usually applied in com bination with chemotherapy or antihormonal therapeutic intervention, potentially prolongs the time to tumor pro gression and or the overall survival rate of palliatively or adjuvantly treated breast cancer patients.

Individual responsiveness, however, cannot be predicted, varies significantly, and spans from de novo to acquired resistance to moderate and high susceptibility. Her1 and Her3 receptor expression in breast cancer has been described to be associated with a poor course and outcome of disease. In contrast, selleck chemicals the prognostic value of Her4 receptor expression is uncertain.