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Targeting the receptor tyrosine kinase RET sensitizes breast cancer cells to tamoxifen treatment and reveals a role for RET in endocrine resistance

Oncogene volume 29, pages 4648–4657 (2010)Cite this article

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Abstract

Endocrine therapy is the main therapeutic option for patients with estrogen receptor (ERα)-positive breast cancer. Resistance to this treatment is often associated with estrogen-independent activation of ERα. In this study, we show that in ERα-positive breast cancer cells, activation of the receptor tyrosine kinase RET (REarranged during Transfection) by its ligand GDNF results in increased ERα phosphorylation on Ser118 and Ser167 and estrogen-independent activation of ERα transcriptional activity. Further, we identify mTOR as a key component in this downstream signaling pathway. In tamoxifen response experiments, RET downregulation resulted in 6.2-fold increase in sensitivity of MCF7 cells to antiproliferative effects of tamoxifen, whereas GDNF stimulation had a protective effect against the drug. In tamoxifen-resistant (TAMR-1) MCF7 cells, targeting RET restored tamoxifen sensitivity. Finally, examination of two independent tissue microarrays of primary human breast cancers revealed that expression of RET protein was significantly associated with ERα-positive tumors and that in primary tumors from patients who subsequently developed invasive recurrence after adjuvant tamoxifen treatment, there was a twofold increase in the number of RET-positive tumors. Together these findings identify RET as a potentially important therapeutic target in ERα-positive breast cancers and in particular in tamoxifen-resistant tumors.

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Acknowledgements

This work was supported by Breakthrough Breast Cancer (CMI, L-AM and MD), the Association of International Cancer Research (grant 09-0533; CMI, AM and IP-M), the Mary-Jean Mitchell Green Foundation (L-AM and MD) and the Ministerio de Educación y Ciencia (MEC) of Spain (grant EX2006-1341; IP-M). We acknowledge NHS funding to the NIHR Biomedical Research Centre. We thank Anne E Lykkesfeldt for the TAMR-1 cells, Jorge Reis-Filho, Suzanne Parry, Kay Savage, Margaret Hills and Janine Salter for their help with the TMA staining and analysis, and to Ana Maria Pereira for her advice on the tamoxifen response experiments.

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  1. I Plaza-Menacho

    Present address: 3Current address: Structural Biology Laboratory, London Research Institute, Cancer Research UK, London WC2A 3PX, UK,

Authors and Affiliations

  1. Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK

    I Plaza-Menacho, A Morandi, D Robertson, S Pancholi, S Drury, M Dowsett, L-A Martin & C M Isacke

  2. Academic Department of Biochemistry, The Royal Marsden Hospital Trust, London, UK

    S Drury & M Dowsett

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  1. I Plaza-Menacho
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Correspondence to C M Isacke.

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Plaza-Menacho, I., Morandi, A., Robertson, D. et al. Targeting the receptor tyrosine kinase RET sensitizes breast cancer cells to tamoxifen treatment and reveals a role for RET in endocrine resistance. Oncogene 29, 4648–4657 (2010). https://doi.org/10.1038/onc.2010.209

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