Plaza-Menacho, I., Morandi, A., Robertson, D., Pancholi, S., Drury, S., Dowsett, M., Martin, L., Isacke, C. M. (2010) Targeting the receptor tyrosine kinase RET sensitizes breast cancer cells to tamoxifen treatment and reveals a role for RET in endocrine resistance. ONCOGENE, 29 (33). pp. 4648-4657. ISSN 0950-9232

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Abstract

Endocrine therapy is the main therapeutic option for patients with estrogen receptor (ER alpha)-positive breast cancer. Resistance to this treatment is often associated with estrogen-independent activation of ER alpha. In this study, we show that in ER alpha-positive breast cancer cells, activation of the receptor tyrosine kinase RET (REarranged during Transfection) by its ligand GDNF results in increased ER alpha phosphorylation on Ser118 and Ser167 and estrogen-independent activation of ER alpha 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 (TAM(R)-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 ER alpha-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 wRET-positive tumors. Together these findings identify RET as a potentially important therapeutic target in ER alpha-positive breast cancers and in particular in tamoxifen-resistant tumors. Oncogene (2010) 29, 4648-4657; doi:10.1038/onc.2010.209; published online 7 June 2010

Item Type:	Article
Authors (ICR Faculty only):	Dowsett, Mitch and Isacke, Clare and Martin, Lesley-Ann
All Authors:	Plaza-Menacho, I., Morandi, A., Robertson, D., Pancholi, S., Drury, S., Dowsett, M., Martin, L., Isacke, C. M.
Uncontrolled Keywords:	RET; breast cancer; endocrine therapy; tamoxifen; estrogen receptor; endocrine resistance;ACTIVATED PROTEIN-KINASE; GROWTH-FACTOR RECEPTOR; ESTROGEN-RECEPTOR; THERAPY RESISTANCE; MCF-7 CELLS; MEDIATED TRANSCRIPTION; GENE-EXPRESSION; CROSS-TALK; SERINE 118; S6 KINASE
Funding Acknowledgement:	Breakthrough Breast Cancer ; Association of International Cancer Research [09-0533]; Mary-Jean Mitchell Green Foundation ; Ministerio de Educacion y Ciencia (MEC) of Spain [EX2006-1341]; NHS
Funding Text:	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 Educacion 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 TAM<SUP>R</SUP>-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.
Research teams:	ICR divisions > Breast Cancer Research > Molecular Cell Biology ICR divisions > Breast Cancer Research > Endocrinology ICR divisions > Molecular Pathology > Endocrinology
Depositing User:	Users 10 not found.
Date Deposited:	23 Sep 2010 15:49
Last Modified:	06 Feb 2014 14:58
URI:	http://publications.icr.ac.uk/id/eprint/9877

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