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Myeloid Cell Leukemia-1 Inversely Correlates with Glycogen Synthase Kinase-3ß Activity and Associates with Poor Prognosis in Human Breast Cancer

¹ Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center; ² Graduate School of Biomedical Sciences, The University of Texas, Houston, Texas; ³ Center for Molecular Medicine, China Medical University Hospital; ⁴ Asia University, Taichung, Taiwan; and ⁵ State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, China

Requests for reprints: Mien-Chie Hung, Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Unit 108, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-3668; Fax: 713-794-0209; E-mail: mhung{at}mdanderson.org.

Myeloid cell leukemia-1 (Mcl-1), an antiapoptotic Bcl-2 family member, is overexpressed in many types of human cancer and associates with cell immortalization, malignant transformation, and chemoresistance. Glycogen synthase kinase-3ß (GSK-3ß), a key component of the Wnt signaling pathway, is involved in multiple physiologic processes such as protein synthesis, tumorigenesis, and apoptosis. Here, we report that expression of Mcl-1 was correlated with phosphorylated GSK-3ß (p-GSK-3ß) at Ser⁹ (an inactivated form of GSK-3ß) in multiple cancer cell lines and primary human cancer samples. In addition, Mcl-1 was strikingly linked with poor prognosis of human breast cancer, in which the high level of Mcl-1 was related to high tumor grade and poor survival of breast cancer patients. Furthermore, we found that activation of GSK-3ß could down-regulate Mcl-1 and was required for proteasome-mediated Mcl-1 degradation. Under some physiologic conditions, such as UV irradiation, anticancer drug treatment, and inhibition of growth factor pathways, Mcl-1 was down-regulated through activation of GSK-3ß. Our results indicate that Mcl-1 stabilization by GSK-3ß inactivation could be involved in tumorigenesis and serve as a useful prognostic marker for human breast cancer. [Cancer Res 2007;67(10):4564–71]

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