Ras/Raf-1/MAPK pathway mediates response to tamoxifen but not chemotherapy in breast cancer patients

McGlynn, L.M., Kirkegaard, T., Edwards, J., Tovey, S., Cameron, D., Twelves, C., Bartlett, J.M.S. and Cooke, T.G. (2009) Ras/Raf-1/MAPK pathway mediates response to tamoxifen but not chemotherapy in breast cancer patients. Clinical Cancer Research, 15(4), pp. 1487-1495. (doi: 10.1158/1078-0432.CCR-07-4967)

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Publisher's URL: http://dx.doi.org/10.1158/1078-0432.CCR-07-4967

Abstract

<b>Purpose</b>: The expression and activation of the Ras/Raf-1/mitogen-activated protein kinase (MAPK) pathway plays an important role in the development and progression of cancer, and may influence response to treatments such as tamoxifen and chemotherapy. In this study we investigated whether the expression and activation of the key components of this pathway influenced clinical outcome, to test the hypothesis that activation of the MAPK pathway drives resistance to tamoxifen and chemotherapy in women with breast cancer. <b>Experimental Design</b>: Breast tumors from patients at the Glasgow Royal Infirmary and others treated within the BR9601 trial were analyzed for expression of the three Ras isoforms, total Raf-1, active and inactive forms of Raf-1 [pRaf(ser338) and pRaf(ser259), respectively], MAPK, and phospho-MAPK using an immunohistochemical approach. Analyses were done with respect to disease free-survival and overall survival. <b>Results</b>: Expression and activation of the Ras pathway was associated with loss of benefit from treatment with tamoxifen but not chemotherapy. Overexpression of pRaf(ser338) was associated with shortened disease-free and overall survival time in univariate analyses. Multivariate analysis suggested pRaf(ser338) was independent of known prognostic markers in predicting outcome following tamoxifen treatment (<i>P</i>=0.03). <b>Conclusion</b>: This study suggests that activation of the Ras pathway predicts for poor outcome on tamoxifen but not chemotherapy, and identifies pRaf(ser338) as a potential marker of resistance to estrogen receptor–targeted therapy. In addition, it suggests that expression of pRaf(ser338) could identify patients for whom tamoxifen alone is insufficient adjuvant systemic therapy, but for whom the addition of chemotherapy may be of benefit.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:McGlynn, Dr Liane and Cooke, Prof Timothy and Edwards, Professor Joanne
Authors: McGlynn, L.M., Kirkegaard, T., Edwards, J., Tovey, S., Cameron, D., Twelves, C., Bartlett, J.M.S., and Cooke, T.G.
Subjects:R Medicine > RC Internal medicine
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Clinical Cancer Research
Publisher:American Association for Cancer Research
ISSN:1078-0432
ISSN (Online):1557-3265
Copyright Holders:Copyright © 2009 American Association for Cancer Research
First Published:First published in Clinical Cancer Research 15(4):1487-1495
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher.

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