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Logo of brcnresBioMed CentralBiomed Central Web Sitesearchsubmit a manuscriptregisterthis articleBreast Cancer Research : BCR
 
Breast Cancer Res. 2010; 12(Suppl 1): O2.
Published online 2010 May 18. doi:  10.1186/bcr2493
PMCID: PMC2875558

Upregulation of ADAM proteases and HER ligands through a feedback loop mediates acquired resistance to trastuzumab in HER2-amplified breast cancer

Introduction

The response rarely sustains long among the responders for Herceptin (trastuzumab) monotherapy treatment. It is still poorly understood how Herceptin exerts its mechanism of action and how the acquired resistance to this drug occurs.

Materials and methods

We used a multidisciplinary approach including fluorescence resonance energy transfer and biochemical methods to assess the effects of Herceptin on various signalling pathways and to determine the acquired resistance mechanisms of Herceptin in various HER2-positive breast cell lines and a BT474 xenograft model.

Results

We have shown that Herceptin does not decrease HER2 phosphorylation despite the effect on HER2 receptor downregulation. HER2 phosphorylation is maintained by the activation of EGFR, HER3 and HER4 via their dimerisation with HER2 in breast cancer cells. The activation of EGFR, HER3 and HER4 is induced by HER ligand release, including heregulin and betacellulin. The release of HER ligands is mediated by ADAM proteases including ADAM17/TACE. Furthermore, we demonstrated that the feedback loop involving HER ligands and ADAM proteases is activated due to a decrease in PKB phosphorylation induced by Herceptin treatment. The feedback loop is also switched on when PKB phosphorylation is decreased by a PKB inhibitor. We have shown that the feedback loop activates the HER receptors and maintains HER2 phosphorylation in response to Herceptin. Herceptin in combination with a panHER inhibitor also caused a much greater tumour inhibition compared with Herceptin or panHER inhibitor alone in the xenograft model.

Conclusions

Our data provide evidence that Herceptin as monotherapy may result in poor outcome for patients due to the escape mechanisms through a feedback loop involving the upregulation of ADAM proteases and HER ligands. We have provided a novel mechanism of acquired resistance to Herceptin in HER2-positive breast cancer and have resolved the inconsistencies in the literature regarding the effect of Herceptin on HER2 phosphorylation.


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