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Departments of Biochemistry and Molecular Biology [T. A. C., Y. J. L., G. M. C.], Cell and Developmental Biology [J. K. D.], and Physiology and Pharmacology [E. E. R., R. H., E. J. K.], Oregon Health Sciences University, Portland, Oregon 97201
We identified an NH2-terminally truncated HER-2/neu product of Mr 95,000 with in vitro kinase activity by Western blotting and immunoprecipitations using domain-specific antibodies. p95 levels correlated with the extracellular domain (ECD) shed from different cells under varied conditions. Both ECD and p95 were at 
20-fold lower levels in SKOV3 ovarian carcinoma cells, as compared to BT474 breast carcinoma cells. Both were stimulated by treatment of cells with the phorbol ester tumor promoter phorbol 12-myristate 13-acetate and the lysosomotrophic agent chloroquine. The hydroxamate inhibitor of metalloproteases, TAPI, suppressed both p95 and ECD in a dose-dependent fashion, with maximal inhibition at 
10 µM in BT474 cells. Cancer tissues were analyzed by Western blotting and scored for p95HER-2/neu and for p185HER-2/neu expression. Breast and ovarian cancer tissues were both found to express p95HER-2/neu in addition to p185HER-2/neu. Of 161 breast cancer tissues, 22.4% expressed p95, 21.7% overexpressed p185, and 14.3% were p95 positive and overexpressed p185. A higher proportion of node-positive patients (23 of 78) than node-negative patients (9 of 63) expressed p95 in all tumors combined (P = 0.032). In the group that overexpressed p185, those that contained p95 were associated with node-positive patients (15 of 21), whereas those that were p95 negative were associated with node-negative patients (8 of 11; P = 0.017). Neither p95- nor p185-rich patients significantly correlated with tumor size or with hormone receptor status in this study. Our findings show that breast cancers, which express the HER-2/neu oncogene, are heterogeneous with respect to HER-2/neu protein products. p95HER-2/neu appears to distinguish tumors that have metastasized to the lymph nodes from those in node-negative patients.
1 Supported by National Cancer Institute Grant CA-71447 and Department of Defense Breast Cancer Research Program Grant DAMD17-6204. J. K. D. is a predoctoral fellow of the Department of Defense Breast Cancer Research Program.
2 The first three authors contributed equally to this work.
3 Present address: Cascade Biologics, Inc., 4475 Southwest Scholls Ferry Road, Portland, OR 97225.
4 To whom requests for reprints should be addressed, at Department of Biochemistry and Molecular Biology, Oregon Health Sciences University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97201. E-mail: clinton@ohsu.edu.
Received 7/ 7/98. Accepted 9/15/98.
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