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Targeting ß-Transducin Repeat–Containing Protein E3 Ubiquitin Ligase Augments the Effects of Antitumor Drugs on Breast Cancer Cells

Departments of ¹ Animal Biology and ² Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and ³ Department of Dermatology, University of Wisconsin, Madison, Wisconsin

Requests for reprints: Serge Y. Fuchs, Department of Animal Biology, University of Pennsylvania, 3800 Spruce Street, Room 161E VET, Philadelphia, PA 19104-6046. Phone: 215-573-6949; Fax: 215-573-5188; E-mail: syfuchs{at}vet.upenn.edu.

ß-Transducin repeat–containing proteins (ß-TrCP) serve as substrate recognition component of E3 ubiquitin ligases that control stability of important regulators of cell cycle and signal transduction. ß-TrCP function is essential for the induction of nuclear factor B transcriptional activities, which play a key role in proliferation and survival of cancer cells and are often constitutively up-regulated in human breast cancers. Here we show that inhibition of ß-TrCP either by RNAi approach or by forced expression of a dominant-negative ß-TrCP mutant suppresses growth and survival of human breast cancer cells. In addition, inhibition of ß-TrCP augments the antiproliferative effects of anticancer drugs such as doxorubicin, tamoxifen, and paclitaxel on human mammary tumor cells. These data provide the proof of principle that targeting ß-TrCP might be beneficial for anticancer therapies.

Key Words: ß-TrCP • ubiquitin • E3 ligase • breast cancer • NFB • therapy

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