Actions and Substrates for the HER4 Tyrosine Kinase in Breast Cancer
Abstract
The EGF receptor family consists of four members (EGFR and HER 2, 3 and 4). One, HER2, is overexpressed in 20-25% of human breast cancers through gene amplification while another, the EGF receptor, is thought to be overexpressed or activated in poor prognosis breast cancers. Our objective was to determine whether the most recently discovered member, HER4, triggers a distinct, anti-proliferative and differentiation signal in breast cell lines and could therefore be a marker breast cancer with a better prognosis. After cloning the HER4 cDNA and constructing various chimeric and mutant receptors, we created novel breast cell lines expressing a variety of molecular constructs. These were used to conclusively demonstrate that HER4 activation stimulated anti-proliferative and differentiation responses in breast cell lines, even in the absence of HER2 signaling. Thus, HER4 is both necessary and sufficient to slow the growth of breast cancer cell lines. Studies in the last year allowed development of microarray technology to delineate the effect of HER4 signaling alone as compared to combined HER2, HER3, HER4 signaling in the control of gene expression. The experiments using the cell lines developed for this project have been performed, and hybridizations to 10,000 cDNA chip arrays have taken place. These arrays are awaiting bioinfomatic analysis. Lastly, we have investigated the role of EGFR vIII as a regulator breast cancer tumorigenesis. We have shown EGFR vIII is capable of phosphorylating HER 4 when co-expressed by transfection but does not appear to do so in the context of overexpression in breast cancer cell lines.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2001
- Accession Number
- ADA398494
Entities
People
- H. S. Earp
Organizations
- University of North Carolina at Chapel Hill