Role of Stat3 and ErbB2 in Breast Cancer
Abstract
Activation of Stat3 has been demonstrated in breast and other cancers. However, the exact mechanisms 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 role of cadherin- 11 engagement using mouse Balb/c3T3 fibroblasts, which have high amounts of Cadherin -11. Cadherin-11 knockdown experiments demonstrated that this increase is required for Stat3 activation. Plating the cells on surfaces functionalised with cadherin-11 derived fragments caused a dramatic increase in Stat3-ptyr705 levels, indicating that cadherin-11 can directly activate Stat3, in the absence of cell to cell contact. Our results also demonstrated a reciprocal regulation between cav1 and Stat3. cav-1 downregulation through expression of shRNA activates Stat3, and conversely, cav1 overexpression downregulates Stat3 and induces growth retardation or apoptosis in mouse fibroblasts, as well as in breast cancer lines. In all cases, apoptosis was inhibited by co-expression of the constitutively active form of Stat3, Stat3C. Taken together, these findings point to cav1 as an inhibitor of Stat3 activity. In addition, it was previously demonstrated that cav1 upregulates p53, although the exact mechanism is unclear. Since Stat3 is known to inhibit p53 transcription through direct promotor binding, these data also point to the possibility that cav1 upregulation may, in fact, activate p53 through Stat3 inhibition. We also further demonstrate for the first time that, in a feedback loop, Stat3 inhibition results in a dramatic increase in cav1 levels, indicating that Stat3 also downregulates cav1 expression. Taken together, our findings reveal the presence of a potent, negative regulatory loop between cav1, p53 and
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2011
- Accession Number
- ADA582549
Entities
People
- Mulu Geletu
Organizations
- Queen's University