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 HCl 1 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 % involve interference with the growth arrest that occurs prior to the induction of differentiation; the mechanism for growth arrest may require the downregulation of Mekl expression. In addition, EGF mitogenic stimulation also inhibits Stat5 binding to its DNA binding site in the beta casein promoter.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2002
- Accession Number
- ADA407463
Entities
People
- Mari G. Cerrito
- Mary L. Cutler
- Treas Chopp
- Weihan Wang
Organizations
- Henry M. Jackson Foundation for the Advancement of Military Medicine