Domain Specific Effects of Herstatin, an Alternative HER-2 (ErbB-2) Product, on ErbB Positive Breast Cancer
Abstract
The role of erbB receptors in breast cancer. The establishment and progression of breast cancer is controlled by receptors for peptide growth factors and for estrogens (I). Of these receptors, the Epidermal Growth Factor Receptor (EGFR) family has been heavily implicated in breast cancer. This type I receptor tyrosine kinase (RTK) family consists of four receptors: EGFR (erbB 1), Human Epidermal growth factor Receptor 2 (HER-2, erbB2), HER-3 (erbB3), and HER-4 (erbB4). These RTKs are transmembrane cell surface glycoproteins that either homo- or hetero-dimerize to signal. The signal transduction cascade commences with growth factor binding, receptor dimerization, and tyrosine autophosphorylation of the cytoplasmic domain. This leads to the recruitment of intracellular signaling effectors that activate the MAPK mitogenic signaling cascade and the AKT survival-signaling cascade(2-4). The erbB growth factor receptors are under tight control in the cell. Disruption of this control leads to aberrant signaling and growth, and converts estrogen-responsive cells to an estrogen-independent state(S). Overexpression of HER-2 is a common molecular abnormality in breast cancer, implicated in 20 - 30% of all cases(6). HER-2 is the preferred heterodimer partner of the erbB receptors. This heterodimerization capacity leads to increased signaling diversity and oncogenic capability, resulting in a pathogenic role for these receptors in breast cancer(7- 10). ErbB directed breast cancer therapies. Due to the erbB receptors' prominent role in carcinogenesis, they have become prime targets for cancer therapies. There are currently several studies on small molecule inhibitors that specifically target the cytoplasmic domain of the EGFR, including ZD1839 and AG1478 (11-14). Herceptin, an inhibitory antibody, specifically targets the ectodomain of HER-2(15).
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2005
- Accession Number
- ADA438605
Entities
People
- Lara Shamieh
Organizations
- Oregon Health & Science University