HER2 Regulation of Angiopoietin-2: A Mechanistic Factor in Metastasis
Annual rept. 1 Sep 2001-1 Sep 2002
MARYLAND UNIV BALTIMORE
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This proposal focuses on two key steps in the metastatic pathway angioinvasion and tumor cell transmigration across the endothelium. HER2 amplification is associated with early tumor dissemination, rapid tumor progression and increased invasiveness. The overall objective of this proposal is to determine if HER2 signaling-induced production of Angiopoietin-2 Ang-2 in breast cancer cells imparts a metastatic advantage,and to determine if overexpression of HER2 in human breast cancer is linked to angiopoietin-2 expression. Specific aim 1 will determine if production of Ang-2 by the HER2 expressing cancer cells induces angioinvasion by testing for microvessel dismantling and transendothelial cell migration by testing for endothelial cell retraction. Specific aim 2 will determine if Angiopoietin-2 is co-expressed with HER2 in human breast cancers, and further to determine if Angiopoietin-2 expression is linked to a specific hetero-dimer of HER2 EGFR, HER3, or HER4. We will employ Laser Capture Microdissection to precisely select cancer cells for study. After selection, RT-PCR technology will be used to detect expression of the mRNAs of interest. The results of the experiments in this proposal will potentially lead to therapeutic interventions to block angiopoietin-2 from promoting tumor metastasis. These interventions may act synergistically with the HerceptinTrademark antibody blockade of HER2. Additionally, this data may assist in selecting which patients would benefit from HerceptinTrademark antibody therapy.
- Anatomy and Physiology
- Medicine and Medical Research