Control of Mammary Differentiation by Ras-Dependent Signal Transduction Pathways
Abstract
Mammary epithelial cells undergo periodic cycles of growth, differentiation and apoptosis during pregnancy and lactation. These processes are initiated by a complex series of signals that include mammotrophic hormones and locally-derived growth factors. This study is aimed at determining the mechanism by which an important mitogenic signal transduction pathway, which is frequently activated in breast carcinoma, inhibits mammary differentiation and apoptosis. We have demonstrated that the Ras pathway is activated by EGF stimulation of HC11 mammary epithelial cells. This occurs in part via the increase in GTP-bound Ras in the cells. EGF stimulation results in activation of Erk and Akt signal transduction pathways and prevents lactogenic differentiation. Inhibition of either Ras (via DNRas expression) or Erk (via PD98059) or Akt (via wortmannin) can counter the effects of EGF on differentiation. The mechanism of disruption of differentiation appears to involve interference with the growth arrest that occurs prior to the induction of differentiation; the mechanism for growth arrest may require the down regulation of Mek1 expression. The expression of dominant negative Ras in HC11 cells blocked signal transduction to the Ras-Raf-Mek-Erk signal transduction pathway but not signal transduction via the PI-3-kinase pathway. Expression studies of HC11 cells undergoing lactogenic differentiation using DNA microarrays demonstrated that there is a shift in gene expression that affects genes related to milk production as well as development and growth control.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2003
- Accession Number
- ADA417953
Entities
People
- Mary L. Cutler
Organizations
- Henry M. Jackson Foundation for the Advancement of Military Medicine