ADAM10 mediates trastuzumab resistance and is correlated with survival in HER2 positive breast cancer

Katharina Feldinger, Daniele Generali, Gabriela Kramer-Marek, Merel Gijsen, Tzi Bun Ng, Jack Ho Wong, Carla Strina, Mariarosa Cappelletti, Daniele Andreis, Ji Liang Li, Esther Bridges, Helen Turley, Russell Leek, Ioannis Roxanis, Jacek Capala, Gillian Murphy, Adrian L. Harris, Anthony Kong

Research output: Contribution to journalArticle

Abstract

Trastuzumab prolongs survival in HER2 positive breast cancer patients. However, resistance remains a challenge. We have previously shown that ADAM17 plays a key role in maintaining HER2 phosphorylation during trastuzumab treatment. Beside ADAM17, ADAM10 is the other well characterized ADAM protease responsible for HER ligand shedding. Therefore, we studied the role of ADAM10 in relation to trastuzumab treatment and resistance in HER2 positive breast cancer. ADAM10 expression was assessed in HER2 positive breast cancer cell lines and xenograft mice treated with trastuzumab. Trastuzumab treatment increased ADAM10 levels in HER2 positive breast cancer cells (p=0.001 in BT474; p=0.01 in SKBR3) and in vivo (p=0.0001) compared to control, correlating with a decrease in PKB phosphorylation. ADAM10 inhibition or knockdown enhanced trastuzumab response in nai¨ve and trastuzumab resistant breast cancer cells. Trastuzumab monotherapy upregulated ADAM10 (p=0.05); and higher pre-treatment ADAM10 levels correlated with decreased clinical response (p=0.05) at day 21 in HER2 positive breast cancer patients undergoing a trastuzumab treatment window study. Higher ADAM10 levels correlated with poorer relapse-free survival (p=0.01) in a cohort of HER2 positive breast cancer patients. Our studies implicate a role of ADAM10 in acquired resistance to trastuzumab and establish ADAM10 as a therapeutic target and a potential biomarker for HER2 positive breast cancer patients.

Original languageEnglish
Pages (from-to)6633-6646
Number of pages14
JournalOncotarget
Volume5
Issue number16
Publication statusPublished - 2014

Keywords

  • ADAM10
  • HER2
  • Resistance
  • Survival
  • Trastuzumab

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Feldinger, K., Generali, D., Kramer-Marek, G., Gijsen, M., Ng, T. B., Wong, J. H., Strina, C., Cappelletti, M., Andreis, D., Li, J. L., Bridges, E., Turley, H., Leek, R., Roxanis, I., Capala, J., Murphy, G., Harris, A. L., & Kong, A. (2014). ADAM10 mediates trastuzumab resistance and is correlated with survival in HER2 positive breast cancer. Oncotarget, 5(16), 6633-6646.