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Annals of Oncology Advance Access published online on August 28, 2009
Annals of Oncology, doi:10.1093/annonc/mdp346
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© The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Growth factor receptor-bound protein-7 (Grb7) as a prognostic marker and therapeutic target in breast cancer

Y. Nadler1, A. M. González2,3, R. L. Camp4, D. L. Rimm4, H. M. Kluger1 and Y. Kluger2,*

1 Department of Medicine, Yale University School of Medicine, New Haven, CT
2 Department of Cell Biology, New York University, New York, NY
3 Computer Science Department, Universidad Autónoma de Madrid, Madrid, Spain
4 Department of Pathology, Yale University School of Medicine, New Haven, USA

* Correspondence to: Dr Y. Kluger, Department of Cell Biology, Skirball Institute, New York University, 540 First Avenue, 3rd Floor, New York, NY 10016, USA. Tel: +1 212-263-8289; Fax: +1 212-263-8160; E-mail: kluger{at}saturn.med.nyu.edu

Background: Growth factor receptor-bound protein-7 (Grb7) is an adapter-type signaling protein recruited to various tyrosine kinases, including HER2/neu. Grb7-specific inhibitors are in early development. As with other targeted therapies, response to therapy might be associated with target expression.

Materials and methods: Tissue microarrays containing 638 primary breast cancer specimens with 15-year patient follow-up were employed to assess Grb7 expression using our Automated QUantitative Analysis method; cytokeratin defines pixels as breast cancer (tumor mask) within the histospot, and Grb7 expression within the mask is measured with Cy5-conjugated antibodies.

Results: High Grb7 expression was strongly associated with decreased survival in the entire cohort and in the node-positive subset (P = 0.0034 and P = 0.0019, respectively). On multivariable analysis, it remained an independent prognostic marker (P = 0.01). High Grb7 was strongly associated with high HER2/neu, and coexpression of these molecules was associated with worse prognosis than HER2/neu overexpression alone.

Conclusions: High Grb7 defines a subset of breast cancer patients with decreased survival, indicating that Grb7 might be a valuable prognostic marker and drug target. Coexpression with HER2/neu indicates that cotargeting these molecules might be an effective approach for treating HER2/neu-positive breast cancers. Future studies using Grb7-targeting agents should include assessment of Grb7 levels.

Grb7, HER2/neu, prognosis, therapeutic targets

Received for publication February 24, 2009. Revision received June 2, 2009. Accepted for publication June 4, 2009.


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