The role of the metastasis suppressor tetraspanin CD82/KAI1 in trastuzumab-mediated cellular responses

McGrowder, Eva (2012). The role of the metastasis suppressor tetraspanin CD82/KAI1 in trastuzumab-mediated cellular responses. University of Birmingham. Ph.D.

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Abstract

The metastasis suppressor CD82/KAI1, a member of the tetraspanin family of transmembrane proteins has previously been shown to associate with ErbB2 (Odintsova et al. 2003). We hypothesised that CD82 could potentiate the efficacy of Herceptin by either regulating the distribution and dynamics of the ErbB2/Herceptin complex or by modifying the recruitment of signalling molecules to the plasma membrane. The role of CD82 in Herceptin-mediated cellular responses was investigated using ErbB2-positive breast cancer cell lines expressing varying levels of CD82. We found that ectopic expression of CD82 resulted in a poor cellular response to Herceptin treatment, redistribution of ErbB2 and an increase in phosphorylation of ErbB2, Src and proteins of the mitogen-activated protein kinase (MAPK) signalling cascade in a manner that was independent of the Ras proteins. The CD82-mediated effect on ErbB signalling was found to be specific to the MAPK pathways, as the phosphoinositide 3-kinase (PI3K) pathway was unaffected by ectopic expression of CD82. Taken together, our results demonstrate that CD82 negatively modulates the cellular response of ErbB2-positive breast cancer cells to Herceptin treatment by not only regulating the distribution of the ErbB2 receptor, but also its phosphorylation and activation of downstream signalling pathways, particularly the MAPK pathway.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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