Regulated Transformation of Mammary Epithelial Cells by Transforming Growth Factor-Beta 1

摘要

Disruptions of transforming growth factor-beta (TGF-Beta) signaling contribute to the development and progression of human breast cancer. TGF-Beta signals through its interaction with two TGF-Beta type II receptors (TBRII) and subsequent recruitment of two type I receptors. In turn, parallel downstream signaling pathways activate SMAD proteins contributing to growth inhibition, as well as RhoA, p38MAPK, and P13-kinase/AKT pathways involved in epithelial to mesenchymal transdifferentiation (EMT). We hypothesized that there may be a different TBRII activation threshold level required for the individual parallel downstream- signaling pathways. We disrupted TGF-Beta signaling in mammary epithelial cells in culture and in mice by the expression of a dominant-negative TBRII (DNIIR). We found that similar DNIIR expression levels resulted in the inhibition of both TOF-Beta-mediated growth inhibition and EMT. However, the threshold for TGF-Beta-mediated SMAD and P13-kinase/AKT activation was inhibited at a lower DNIIR expression level than that required for inhibiting the p38MAPK pathway. The transgenic expression of DNIIR in mice resulted in the development of spontaneous tumors. Interestingly DNIIR expression was undetecible specifically in the invasive tumors. Together the results support our initial hypothesis of differential TBRII activation thresholds and further suggest a role for TGF-Beta in EMT potentially to facilitate metastasis.