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Title: Herceptin resistance in HER2-moderately expressed breast cancer
Author: Kerry, Jonathan Benjamin
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2012
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HER2 overexpression occurs in approximately 15-20% of all breast cancers and is associated with poor prognosis. The development of Herceptin, a monoclonal antibody against HER2, has been significant in prolonging survival of these patients. Herceptin is less efficient in patients who do not overexpress HER2, so-called HER2-negative, such that they are not eligible for treatment with this drug. An incomplete understanding of Herceptin action and HER2 classification means that these patients may unnecessarily be being denied targeted therapy. In this thesis I show that an inability of Herceptin to maintain decreased HER3 and AKT activation in a subset of HER2-negative breast cancer cell lines (those that are HER2 2+, or HER2-moderately expressed) is responsible for reduced response. Surprisingly HER3 activation may also have a role in propagating the effects of Herceptin in these cells, making this receptor a central player. This study also shows that HER2-moderately expressed cells can rely heavily on ADAM-mediated ErbB receptors for normal survival and that targeting these by means of ADAM or tyrosine kinase inhibitors may present a better therapeutic option for these patients.
Supervisor: Kong, Anthony Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Oncology