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Journal of Cancer Research and Clinical Oncology

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01-01-2016 | Original Article – Cancer Research

Amphiregulin confers trastuzumab resistance via AKT and ERK activation in HER2-positive breast cancer

Authors: Ji-Won Kim, Debora K. Kim, Ahrum Min, Kyung-Hun Lee, Hyun-Jin Nam, Jee Hyun Kim, Jin-Soo Kim, Tae-Yong Kim, Seock-Ah Im, In Ae Park

Published in: Journal of Cancer Research and Clinical Oncology | Issue 1/2016

Abstract

Purpose

Human epidermal growth factor receptor 2 (HER2) heterodimerizes and shares common signaling pathways with epidermal growth factor receptor (EGFR). In this study, we investigated the clinical implication of amphiregulin, a ligand for EGFR, on trastuzumab therapy in HER2-positive breast cancer.

Methods

Serum amphiregulin levels were quantified in 50 consecutive patients with HER2-positive metastatic breast cancer who received first-line trastuzumab plus taxane chemotherapy between October 2004 and July 2009. In addition, in vitro experiments were carried out to validate the results.

Results

The median serum amphiregulin level was 1.0 ng/mL with a maximum level of 4.4 ng/mL. Patients with high serum amphiregulin levels (≥0.5 ng/mL) had significantly shorter progression-free survival (15.1 months vs. not reached; P = 0.018). Colony-forming assays demonstrated that the addition of amphiregulin resulted in increased proliferation of cells. In addition, the anti-proliferative effect of trastuzumab was decreased in the presence of amphiregulin. Western blot analysis showed that amphiregulin activated AKT and ERK pathways. In addition, in the presence of amphiregulin, sustained phosphorylation of AKT and ERK pathways was observed after trastuzumab treatment.

Conclusions

High serum amphiregulin levels were associated with early disease progression in these patients, possibly due to AKT and ERK signaling activation by amphiregulin.

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Title: Amphiregulin confers trastuzumab resistance via AKT and ERK activation in HER2-positive breast cancer
Authors: Ji-Won Kim
Debora K. Kim
Ahrum Min
Kyung-Hun Lee
Hyun-Jin Nam
Jee Hyun Kim
Jin-Soo Kim
Tae-Yong Kim
Seock-Ah Im
In Ae Park
Publication date: 01-01-2016
Publisher: Springer Berlin Heidelberg
Published in: Journal of Cancer Research and Clinical Oncology / Issue 1/2016
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-015-2012-4

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