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


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.
Nadler
Y
Y
Department of Medicine, Yale University School of Medicine, New Haven, CT.
González
A M
AM
Department of Cell Biology, New York University, New York, NY; Computer Science Department, Universidad Autónoma de Madrid, Madrid, Spain.
Camp
R L
RL
Department of Pathology, Yale University School of Medicine, New Haven, USA.
Rimm
D L
DL
Department of Pathology, Yale University School of Medicine, New Haven, USA.
Kluger
H M
HM
Department of Medicine, Yale University School of Medicine, New Haven, CT.
Kluger
Y
Y
Department of Cell Biology, New York University, New York, NY. Electronic address: kluger@saturn.med.nyu.edu.
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism* / Q000473:pathology; D018275:Carcinoma, Lobular / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005455:Fluorescent Antibody Technique; D005500:Follow-Up Studies; D051382:GRB7 Adaptor Protein / Q000378:metabolism*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008875:Middle Aged; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015996:Survival Rate; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured; D055815:Young Adult
D014408:Biomarkers, Tumor; D051382:GRB7 Adaptor Protein; D018719:Erb-b2 Receptor Tyrosine Kinases; C495955:GRB7 protein, human