Differential osteopontin expression in phenotypically distinct subclones of murine breast cancer cells mediates metastatic behavior

被引:41
作者
Mi, ZY [1 ]
Guo, HT [1 ]
Wai, PY [1 ]
Gao, CJ [1 ]
Wei, JP [1 ]
Kuo, PC [1 ]
机构
[1] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA
关键词
D O I
10.1074/jbc.M407952200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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收藏
页码:46659 / 46667
页数:9
相关论文
共 38 条
[1]  
Agrawal D, 2002, J NATL CANCER I, V94, P513
[2]  
Attur MG, 2001, ARTHRITIS RHEUM-US, V44, P578, DOI 10.1002/1529-0131(200103)44:3<578::AID-ANR106>3.0.CO
[3]  
2-7
[4]  
BAUTISTA DS, 1994, J BIOL CHEM, V269, P23280
[5]  
BROWN LF, 1994, AM J PATHOL, V145, P610
[6]   Differential expression of osteopontin and bone sialoprotein in bone metastasis of breast and prostate carcinoma [J].
Carlinfante, G ;
Vassiliou, D ;
Svensson, O ;
Wendel, M ;
Heinegård, D ;
Andersson, G .
CLINICAL & EXPERIMENTAL METASTASIS, 2003, 20 (05) :437-444
[7]   Inactivation of the PTEN gene protein product is associated with the invasiveness and metastasis, but not angiogenesis, of breast cancer [J].
Chung, MJ ;
Jung, SH ;
Lee, BJ ;
Kang, MJ ;
Lee, DG .
PATHOLOGY INTERNATIONAL, 2004, 54 (01) :10-15
[8]   Correlation of osteopontin protein expression and pathological stage across a wide variety of tumor histologies [J].
Coppola, D ;
Szabo, M ;
Boulware, D ;
Muraca, P ;
Alsarraj, M ;
Chambers, AF ;
Yeatman, TJ .
CLINICAL CANCER RESEARCH, 2004, 10 (01) :184-190
[9]   THE MURINE GENE ENCODING SECRETED PHOSPHOPROTEIN-1 (OSTEOPONTIN) - PROMOTER STRUCTURE, ACTIVITY, AND INDUCTION INVIVO BY ESTROGEN AND PROGESTERONE [J].
CRAIG, AM ;
DENHARDT, DT .
GENE, 1991, 100 :163-171
[10]   Osteopontin stimulates cell motility and nuclear factor κB-mediated secretion of urokinase type plasminogen activator through phosphatidylinositol 3-kinase/Akt signaling pathways in breast cancer cells [J].
Das, R ;
Mahabeleshwar, GH ;
Kundu, GC .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (31) :28593-28606