Role of Stat3 and ErbB2 in Breast Cancer
Abstract
Stat3 is activated by cytokine receptors as well as receptor and non-receptor tyrosine kinases. Activation of Stat3 has been demonstrated in breast and other cancers, while a constitutively active form of Stat3, Stat3C, is able to transform cultured cells, further pointing to an etiologic role for Stat3 in these tumors. 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. A quantitative RT-PCR array experiment using mouse breast epithelial HC11 cells demonstrated a dramatic increase in the levels of secreted IL6 family cytokines, while knockdown experiments demonstrated that this increase is required for Stat3 activation. We also demonstrated that density causes a dramatic increase in levels and activity of the Rac GTPase, due to inhibition of proteasomal degradation. Furthermore, we demonstrated that expression of mutationally activated Rac(exp V12) leads to Stat3 activation through IL6 secretion, and this is required for cell motility, indicating that the gp130/Stat3 axis represents an essential effector for the regulation of key cellular functions. Examination of the role of Stat3 in confluent cultures showed that Stat3 inhibition leads to a dramatic activation of the p53 anti-oncogene. Interestingly, our results also showed that Stat3 inhibition in normal breast epithelial cells induced the p53 target, p21(exp CIP/WAF) but only at lower densities, consistent with previous results showing that p21(exp CIP/WAF) is associated with p53-mediated growth arrest.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2010
- Accession Number
- ADA536626
Entities
People
- Mulu Geletu
Organizations
- Queen's University