Differential Osteopontin Expression in Phenotypically Distinct Subclones of Murine Breast Cancer Cells Mediates Metastatic Behavior

• Published in: The Journal of biological chemistry Vol. 279; no. 45; pp. 46659 - 46667
• Main Authors: Mi, Zhiyong, Guo, Hongtao, Wai, Philip Y, Gao, Chengjiang, Wei, Junping, Kuo, Paul C
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 05-11-2004
• Subjects: Animals; Binding Sites; Biotin - pharmacology; Blotting, Northern; Blotting, Western; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cell Nucleus - metabolism; Dimerization; DNA Mutational Analysis; Humans; Immunoblotting; JNK Mitogen-Activated Protein Kinases - metabolism; Luciferases - metabolism; Mammary Neoplasms, Animal - metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mutation; Neoplasm Invasiveness; Neoplasm Metastasis; Osteopontin; Phenotype; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Promoter Regions, Genetic; RNA, Messenger - metabolism; Sialoglycoproteins - biosynthesis; Signal Transduction; Streptavidin - pharmacology; Transcription Factor AP-1 - metabolism; Transcription, Genetic; Transfection; Up-Regulation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M407952200

Cancer progression depends on an accumulation of metastasis-supporting cell signaling molecules, which target signal transduction
pathways and, ultimately, gene expression. One such molecule, osteopontin (OPN), represents a key molecular signaling event
in tumor progression and metastasis. However, the transcriptional regulatory mechanisms that underlie OPN expression in the
setting of breast cancer have not been well studied. In this regard, we have examined the differential transcriptional regulation
of OPN in the murine mammary epithelial tumor cell lines, 4T1 and 4T07, which are sublines derived from the parental population
of 410.4 cells from Balb/cfC3H mice. These lines are phenotypically heterogeneous in their metastatic behavior. 4T1 hematogenously
metastasizes to the lung, liver, bone, and brain, whereas 4T07 is highly tumorigenic but fails to metastasize. The tumor growth
and metastatic spread of 4T1 cells closely mimics stage IV breast cancer. We demonstrate that a Ras-independent, phosphoinositide-3
kinase-dependent, c-Jun N-terminal kinase-dependent phosphorylation of c-Jun results in binding of an AP-1 c-Jun homodimer
to the OPN promoter in 4T1 cells. This differential up-regulation of OPN gene transcription and protein expression in 4T1
cells conveys in vitro correlates of a metastatic phenotype. These results provide new insight into the transcriptional regulation of OPN as a key
mediator of metastatic behavior in malignancy.