The tyrosine kinase receptor HER2/neu (ErbB2) plays fundamental roles in the development, proliferation and differentiation processes. Overexpression of ErbB2 is present in 25%--30% of breast cancers and is associated with poor prognosis. Trastuzumab (Herceptin), a humanized anti-ErbB2 antibody used to treat ErbB2-overexpressing breast cancer, is often cited as a prototype for rationally-designed anti-neoplastic drugs targeting critical signal transduction pathways. However, development of resistance to trastuzumab is common, and the duration of the clinical response rarely exceeds 12 months. The insulin-like growth-I receptor (IGF-IR) is a transmembrane tyrosine kinase receptor activated by binding of the IGF ligands. The IGF-IR signaling provokes mitogenic and antiapoptotic effects in a number of normal and transformed cell types. IGF-I receptors and ErbB2 receptors share several common signaling transduction pathways, which raises the possibility of interaction between two signaling pathways on modulation of cell proliferation, survival and differentiation. This thesis provides evidence that cross-talk exists between the IGF-IR and ErbB2 signaling pathways and this is associated with trastuzumab resistance. We show here that MCF7/HER2--18 cells which overexpress ErbB2 receptors and express IGF-IR are responsive to trastuzumab treatment only when IGF-IR signaling is minimized. SKBR3 cells genetically altered to overexpress IGF-IR lose sensitivity to trastuzumab treatment in the presence of IGF-I. In the second part of this thesis, we examine the mechanisms by which IGF-IR activation antagonizes the effects of trastuzumab on cell cycle regulation. We show that IGF-I reproducibly reduces the trastuzumab-induced increase of p27 Kip1, decreases association of p27Kip1 with CDK2, and dramatically increases CDK2 activity in IGF-IR-overexpressing SKBR3 cells. In the last part of this thesis, a trastuzumab-resistant SKBR3 cell line was establishe
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.84287 |
| Date | January 2004 |
| Creators | Lu, Yuhong |
| Contributors | Pollak, Michael (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Division of Experimental Medicine.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002141022, proquestno: AAINQ98312, Theses scanned by UMI/ProQuest. |
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