Domain Specific Effects of Herstatin, an Alternative HER-2 (erbB-2) Product, on erbB Positive Breast Cancer

摘要

Herstatin an autoinhibitor of ErbB receptors is produced from an alternatively spliced HER-2 mRNA. Retention and read-through of intron 8 leads to the production of the inhibitory secreted ligand which contains a novel receptor binding domain (RBD) encoded by the intron. Both herstatin and its intron-encoded RBD bind to all four members of the ErbB receptor family. Herstatin also binds to both the lGF-lR and the Insulin Receptor (IR) albeit with approximately 10- fold reduced affinity compared to EGFR and HER-2. Examination of signaling and growth in parental MCF7 breast carcinoma cells and MCF7 cells stably transfected with herstatin revealed that herstatin expression resulted in altered signaling and reduced lGF-l- or Insulin-stimulated proliferation in vitro. These studies demonstrate that in addition to binding to and blocking activation of the EGF receptor family herstatin binds to the lGF-lR and IR and modulates lGF-l- stimulated proliferation and survival signaling either through direct interaction with the lGF-lR or indirectly by modulating crosstalk with the EGF family of receptors. In summary herstatin is a unique ligand of both the EGF and lGF-l reception families that functions to modulate the action of these receptors and may be critical in controlling the progression of ErbB positive breast cancer.