Overexpression of the HER2 receptor occurs in about 15-20% of all breast cancers and is correlated with poor prognosis. Trastuzumab (Herceptin®), a monoclonal antibody targeting HER2, was shown to prolong survival of these patients. However, primary or acquired resistance remains a drawback for the drug. Understanding the mechanisms behind Herceptin resistance is crucial in order to increase the efficacy of the treatment. Many factors have been shown to contribute to resistance, including the protein family of the ADAMs (a disintegrin and metalloproteinase). One of them, ADAM10, cleaves several pro-ligands for the HER-family, such as betacellulin and HB-EGF. It is also responsible for shedding the extracellular domain of HER2. The objective of my M.Sc. is to understand the role of ADAM10 in relation to Herceptin treatment and resistance. In this thesis, it was shown that Herceptin treatment increased ADAM10 levels via an AKT/PKB feedback loop in HER2 positive cells and xenograft tumour samples and that ADAM10 was increased in Herceptin resistant cell lines. The increase of ADAM10 was correlated with an upregulation of the ligand betacellulin in the media. Inhibition of ADAM10 enzymatic activity or knockdown of the protein decreased the activation of HER family members and downstream markers in sensitive and resistant cell lines and was additive to Herceptin treatment in decreasing cell viability in sensitive cells. The TMA samples from a cohort of HER2 positive breast cancer patients have been stained for ADAM10 expression and positive staining was significantly correlated to poorer relapse free as well as overall survival. Both in vitro and in vivo data of this project suggested an important role of ADAM10 in Herceptin treatment of HER2 positive breast cancer.</p
