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

  • Original Article – Cancer Research
  • Published:
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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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Acknowledgments

This research was supported by a grant from the Seoul National University Hospital Research Fund (03-2010-0190) and a grant from the Korea Health Technology R & D Project (HR14C0003) through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Korea.

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Authors and Affiliations

  1. Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumi-ro-173-beon-gil, Seongnam, 463-707, Korea

    Ji-Won Kim & Jee Hyun Kim

  2. Seoul International School, 15 Seongnam-daero-1518-beon-gil, Seongnam, 461-830, Korea

    Debora K. Kim

  3. Cancer Research Institute, Seoul National University, 103 Daehak-ro, Jongno-gu, Seoul, 110-799, Korea

    Ahrum Min, Kyung-Hun Lee, Hyun-Jin Nam, Tae-Yong Kim, Seock-Ah Im & In Ae Park

  4. Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, Korea

    Kyung-Hun Lee, Tae-Yong Kim & Seock-Ah Im

  5. Department of Internal Medicine, SMG-SNU Boramae Medical Center, 20 Boramae-ro-5-gil, Seoul, 156-707, Korea

    Jin-Soo Kim

  6. Department of Pathology, Seoul National University Hospital, 101 Daehak-ro, Seoul, 110-744, Korea

    In Ae Park

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  1. Ji-Won Kim
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  2. Debora K. Kim
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  3. Ahrum Min
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Correspondence to Ahrum Min or Kyung-Hun Lee.

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The authors declare that they have no conflict of interest.

Ethical standard

Signed informed consent for chemotherapy and blood sample collection for the pharmacogenomic study was obtained from all patients before treatment. This study protocol was reviewed and approved by the IRB of the Seoul National University Hospital (IRB Registration No. H-0907-060-287) and conducted in accordance with the precepts established by the Helsinki Declaration.

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Kim, JW., Kim, D.K., Min, A. et al. Amphiregulin confers trastuzumab resistance via AKT and ERK activation in HER2-positive breast cancer. J Cancer Res Clin Oncol 142, 157–165 (2016). https://doi.org/10.1007/s00432-015-2012-4

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  • DOI: https://doi.org/10.1007/s00432-015-2012-4

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