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 determined the mechanism by which Ras activation, an important mitogenic signal transduction pathway that 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. EGF stimulation results in activation of Erk and Akt signal transduction pathways and prevents lactogenic differentiation. Inhibition of either Ras, Erk or Akt can counter the effects of EGF on lactogenic differentiation. Expression of DNRas in HC11 cells enhances Stat5 phophorylation and DNA binding; this results in increased lactogenic differentiation as measured by elevated beta casein transcription, lipid synthesis and mammosphere formation. Using DNA microarray analysis global changes in gene expression were measured in HC11 cells undergoing lactogenic differentiation. Using the same technology genes whose expression was altered by EGF stimulation during differentiation were identified. This information provides an expression profile of gene regulation during lactogenic differentiation of HC11 cells, and identified novel targets in breast tissue exposed to mitogens.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2004
- Accession Number
- ADA427276
Entities
People
- Mary Lou Cutler
Organizations
- Henry M. Jackson Foundation for the Advancement of Military Medicine