STAT5A Regulates the Survival of Mammary Epithelial Cells and the Development of Mammary Cancer
Abstract
Members of the epidermal growth factor receptor (EGFR) family play a significant role in the initiation and progression of mammary epithelial cell transformation. EGFR stimulation can initiate mitogenic signaling through STAT proteins, particularly Stat5a and Stat3. Previously, we have reported that in the presence of an activated EGFR, deletion of Stat5a from the mammary epithelium, delayed mammary involution by 9 days, and hyperplasia and mammary tumor development by 6 weeks. These observations demonstrate that Stat5a is a survival factor and is involved in delaying mammary tumorigenesis. To evaluate the role of Stat5a and Stat3 in breast tumorigenesis, we examined Stat5a and Stat3 protein expression and activation in breast tumors derived from MMTV-Neu, MMTV-Py-V-MT and MMTV-int3 transgenic mice. We found that the tyrosine phosphorylation level of both Stat5a and Stat3 were elevated in MMTV-Neu breast tumors. To understand how the EGFR and its downstream kinase signaling pathway contributes to mammary epithelial cell transformation, we used the ErbB kinase inhibitor, AGl478; MAPK kinase (MEM) inhibitor, PD98O59; Src kinase inhibitor, PP2; and Jak2/3 kinase inhibitor, AG490 in ErbB2-dependent BT- 474, SKBR-3, and MDA-MB-23l human breast cancer cells. Treatment of these cell lines in vitro with the kinase inhibitors resulted in reversible Gl arrest in BT-474 and MDA-MB-231 cells. We are utilizing unique combinations of transgenic(MMTV-Neu) and knockout (Stat3 conditional KO and Stat5a null) mouse models to address the specific contribution of Stat5a and Stat3 in mammary epithelial transformation in vivo. Together these experiments will allow us to evaluate the contribution of these proteins in the initiation and progression of EGFR dependent mammary tumorigenesis.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2002
- Accession Number
- ADA408678
Entities
People
- Brian Bierie
- Robin Humphreys
- Yongzhi Cui
Organizations
- National Institutes of Health