Role of Stat3 and ErbB2 in Breast Cancer.

摘要

Activation of Stat3 has been demonstrated in breast and other cancers. However, the exact mechanism of its activation as well as the role of Stat3 in these tumors, remain to be determined. This study focuses on the identification of the upstream activators of Stat3 in confluent cells as well as the role of Stat3 in this setting. To explore the nature of cell to cell adhesion molecules responsible for Stat3 activation in breast cancer, we examined the effect of cadherin- 11 engagement using mouse Balb/c3T3 fibroblasts, which have high amounts of Cadherin -11, upon Stat3-ptyr705 levels and activity. Cadherin-11 knockdown experiments demonstrated that cadherin11 is required for Rac and Stat3 activation at high cell densities and is necessary for cell survival and migration. We also further demonstrate for the first time that the mesenchymal, class I cadherin, N-cadherin whose activation correlates with metastasis, can also trigger a dramatic surge in Stat3. The fact that the mesenchymal cadherin-11 and N-cadherin may actually activate Stat3, although, contrary to the epithelial E-cadherin, they generally promote metastasis, may point to Stat3 as a central survival, rather than metastasis factor. Our resaults further demonstrate that the cadherin11/Stat3 axis may be necessary for transformation by Src, by being required to inhibit apoptosis triggered by the E2F transcription factor family, which is an indirect target of Src and a number of other oncogenes. Taken together, these data suggest that interference with cadherin-11 or N-cadherin function could induce apoptosis through Stat3 inhibition in metastatic cells specifically, a fact which could have important therapeutic implications.