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Jun Activation Domain-binding Protein 1 Expression in Breast Cancer Inversely Correlates with the Cell Cycle Inhibitor p27^{Kip1 1}

Departments of Molecular Therapeutics [M. A. K., L. T., F-X. C.] and Molecular and Cellular Oncology [R. K.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, and Laboratory of Histology and Embryology, University of Athens School of Medicine, Athens, Greece [G. Z. R., C. K.]

The Jun activation domain-binding protein 1 (JAB1), aside from being an activator protein 1 coactivator, is involved in degradation of the cyclin-dependent kinase inhibitor p27. We examined JAB1 and p27 protein expression in invasive breast carcinoma specimens and the association of this expression with clinical outcome. JAB1 was detected immunohistochemically in 43 of 53 (81%) tumors; 32 (60%) breast carcinomas showed high JAB1 expression (>50% of cells positive) and reduced or absent p27 levels (P = 0.02, Mann-Whitney U test). Tumors with high p27 expression were rarely positive for JAB1. All eight patients with JAB1-negative tumors had no evidence of relapse or disease progression at a median follow-up of 70 months. Immunoblotting showed strong JAB1 expression in breast carcinoma samples but not in paired normal breast epithelial samples. Targeted overexpression of JAB1 by regulated adenovirus in breast cancer cell lines also reduced p27 levels by accelerating degradation of p27. Thus, the JAB1:p27 ratio may be a novel indicator of aggressive, high-grade tumor behavior, and control of JAB1 could be a novel target for experimental therapies.

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