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[Cancer Research 62, 3538-3543, June 15, 2002]
© 2002 American Association for Cancer Research

Tumor Biology

Transformation of Mammary Epithelial Cells by 3-Phosphoinositide-dependent Protein Kinase-1 (PDK1) Is Associated with the Induction of Protein Kinase C{alpha}1

Xiao Zeng, Hangmin Xu and Robert I. Glazer2

Departments of Pharmacology and Oncology, Lombardi Cancer Center, Georgetown University School of Medicine, Washington, DC 20007

3-Phosphoinositide-dependent protein kinase 1 (PDK1) is a mediator of multiple signaling pathways coupled to growth factor receptor activation in human cancers. To evaluate the role of PDK1 in mammary gland oncogenesis, COMMA-1D mouse mammary epithelial cells were retrovirally transduced with PDK1, and transformation was measured by anchorage-independent growth in soft agar. PDK1-expressing cells exhibited a high degree of transformation that was associated with the activation of Akt1 and an elevation of protein kinase C{alpha} (PKC{alpha}) expression. Cells overexpressing Akt1 did not exhibit anchorage-independent growth, whereas PKC{alpha} overexpression produced significant transformation, although to a lesser extent compared with PDK1. Coexpression of Akt1 and PKC{alpha} led to a more than additive effect on transformation activity. Isografts of either PDK1- or PKC{alpha}-expressing cells but not Akt1-expressing cells in syngeneic mice led to formation of poorly differentiated mammary carcinomas. PDK1 was highly expressed in a majority of human breast cancer cell lines. These results suggest that activation of PDK1 can lead to mammary tumorigenesis, in part through PKC{alpha}, and that PDK1 expression may be an important target in human breast cancer.




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