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Molecular and Cellular Biology, September 2003, p. 6507-6519, Vol. 23, No. 18
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.18.6507-6519.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Growth Factor Signaling Induces Metastasis Genes in Transformed Cells: Molecular Connection between Akt Kinase and Osteopontin in Breast Cancer

Guoxin Zhang,1,{dagger} Bin He,1 and Georg F. Weber1,2*

Department of Radiation Oncology, New England Medical Center,1 Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts2

Received 10 December 2002/ Returned for modification 20 February 2003/ Accepted 19 June 2003

Malignant tumors are characterized by excessive growth, immortalization, and metastatic spread, whereas benign tumors do not express gene products that mediate invasion. The molecular basis for this difference is incompletely understood. We have screened signal transduction molecules associated with the epidermal growth factor (EGF) receptor and have identified constitutive phosphorylation, indicative of activation, of Akt kinase in MT2994 breast cancer cells. In contrast, cells of the benign breast epithelial cell lines Comma-D and FSK-7 are immortalized through pathways that are independent of the EGF-phosphatidylinositol 3-kinase-Akt kinase cascade, but this is not associated with invasiveness. Transfection of constitutively active Akt kinase causes accelerated cell division and osteopontin expression. Conversely, dominant-negative Akt kinase slows cell cycle progression and suppresses osteopontin expression. The manipulation of osteopontin expression in this setting by transfection of the gene or its antisense does not affect the growth rate of the cells but alters cell motility and anchorage independence. Therefore, Akt kinase activates two distinct genetic programs: the program of growth and survival, which is independent of osteopontin expression, and the program of invasiveness and anchorage independence, which is mediated by osteopontin. These studies define Akt kinase as a molecular bridge between cell cycle progression and dissemination.

* Corresponding author. Mailing address: Department of Radiation Oncology, New England Medical Center and Tufts University Medical School, 750 Washington St., NEMC #824, Boston, MA 02111. Phone: (617) 636-9013. Fax: (617) 636-1766. E-mail: gweber{at}tufts-nemc.org.

{dagger} Present address: Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People's Republic of China.

Molecular and Cellular Biology, September 2003, p. 6507-6519, Vol. 23, No. 18
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.18.6507-6519.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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