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BMC Cancer
Published in: BMC Cancer 1/2007

Open Access 01-12-2007 | Research article

Critical role of c-Jun overexpression in liver metastasis of human breast cancer xenograft model

Authors: Yan Zhang, Xiaoyun Pu, Ming Shi, Liyong Chen, Yuhua Song, Lu Qian, Guogang Yuan, Hao Zhang, Ming Yu, Meiru Hu, Beifen Shen, Ning Guo

Published in: BMC Cancer | Issue 1/2007

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Abstract

Background

c-Jun/AP-1 has been linked to invasive properties of aggressive breast cancer. Recently, it has been reported that overexpression of c-Jun in breast cancer cell line MCF-7 resulted in increased AP-1 activity, motility and invasiveness of the cells in vitro and tumor formation in nude mice. However, the role of c-Jun in metastasis of human breast cancer in vivo is currently unknown.

Methods

To further investigate the direct involvement of c-Jun in tumorigenesis and metastasis, in the present study, the effects of c-Jun overexpression were studied in both in vitro and in nude mice.

Results

Ectopic overexpression of c-Jun promoted the growth of MCF-7 cells and resulted in a significant increase in the percentage of cells in S phase and increased motility and invasiveness. Introduction of c-Jun gene alone into weakly invasive MCF-7 cells resulted in the transfected cells capable of metastasizing to the nude mouse liver following tail vein injection.

Conclusion

The present study confirms that overexpression of c-Jun contributes to a more invasive phenotype in MCF-7 cells. It indicates an interesting relationship between c-Jun expression and increased property of adhesion, migration and in vivo liver metastasis of MCF-7/c-Jun cells. The results provide further evidence that c-Jun is involved in the metastasis of breast cancer. The finding also opens an opportunity for development of anti-c-Jun strategies in breast cancer therapy.
Appendix
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Literature
1.
Shaulian E, Karin M: AP-1 in cell proliferation and survival. Oncogene. 2001, 20 (19): 2390-2400. 10.1038/sj.onc.1204383.CrossRefPubMed
2.
Shaulian E, Karin M: AP-1 as a regulator of cell life and death. Nat Cell Biol. 2002, 4 (5): E131-6. 10.1038/ncb0502-e131.CrossRefPubMed
3.
Angel P, Karin M: The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim Biophys Acta. 1991, 1072 (2-3): 129-157.PubMed
4.
Angel P, Allegretto EA, Okino ST, Hattori K, Boyle WJ, Hunter T, Karin M: Oncogene jun encodes a sequence-specific trans-activator similar to AP-1. Nature. 1988, 332 (6160): 166-171. 10.1038/332166a0.CrossRefPubMed
5.
Bohmann D, Bos TJ, Admon A, Nishimura T, Vogt PK, Tjian R: Human proto-oncogene c-jun encodes a DNA binding protein with structural and functional properties of transcription factor AP-1. Science. 1987, 238 (4832): 1386-1392. 10.1126/science.2825349.CrossRefPubMed
6.
Halazonetis TD, Georgopoulos K, Greenberg ME, Leder P: c-Jun dimerizes with itself and with c-Fos, forming complexes of different DNA binding affinities. Cell. 1988, 55 (5): 917-924. 10.1016/0092-8674(88)90147-X.CrossRefPubMed
7.
Hartl M, Vogt PK: Oncogenic transformation by Jun: role of transactivation and homodimerization. Cell Growth Differ. 1992, 3 (12): 899-908.PubMed
8.
Abate C, Curran T: Encounters with Fos and Jun on the road to AP-1. Semin Cancer Biol. 1990, 1 (1): 19-26.PubMed
9.
Curran T, Franza BR: Fos and Jun: the AP-1 connection. Cell. 1988, 55 (3): 395-397. 10.1016/0092-8674(88)90024-4.CrossRefPubMed
10.
Angel P, Imagawa M, Chiu R, Stein B, Imbra RJ, Rahmsdorf HJ, Jonat C, Herrlich P, Karin M: Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor. Cell. 1987, 49 (6): 729-739. 10.1016/0092-8674(87)90611-8.CrossRefPubMed
11.
Lamph WW, Wamsley P, Sassone-Corsi P, Verma IM: Induction of proto-oncogene JUN/AP-1 by serum and TPA. Nature. 1988, 334 (6183): 629-631. 10.1038/334629a0.CrossRefPubMed
12.
Lee W, Mitchell P, Tjian R: Purified transcription factor AP-1 interacts with TPA-inducible enhancer elements. Cell. 1987, 49 (6): 741-752. 10.1016/0092-8674(87)90612-X.CrossRefPubMed
13.
Kaibuchi K, Fukumoto Y, Oku N, Hori Y, Yamamoto T, Toyoshima K, Takai Y: Activation of the serum response element and 12-O-tetradecanoylphorbol-13-acetate response element by the activated c-raf-1 protein in a manner independent of protein kinase C. J Biol Chem. 1989, 264 (35): 20855-20858.PubMed
14.
Rauscher FJ, Voulalas PJ, Franza BR, Curran T: Fos and Jun bind cooperatively to the AP-1 site: reconstitution in vitro. Genes Dev. 1988, 2 (12B): 1687-1699. 10.1101/gad.2.12b.1687.CrossRefPubMed
15.
Alani R, Brown P, Binetruy B, Dosaka H, Rosenberg RK, Angel P, Karin M, Birrer MJ: The transactivating domain of the c-Jun proto-oncoprotein is required for cotransformation of rat embryo cells. Mol Cell Biol. 1991, 11 (12): 6286-6295.CrossRefPubMedPubMedCentral
16.
Johnson R, Spiegelman B, Hanahan D, Wisdom R: Cellular transformation and malignancy induced by ras require c-jun. Mol Cell Biol. 1996, 16 (8): 4504-4511.CrossRefPubMedPubMedCentral
17.
Mechta F, Lallemand D, Pfarr CM, Yaniv M: Transformation by ras modifies AP1 composition and activity. Oncogene. 1997, 14 (7): 837-847. 10.1038/sj.onc.1200900.CrossRefPubMed
18.
Schutte J, Minna JD, Birrer MJ: Deregulated expression of human c-jun transforms primary rat embryo cells in cooperation with an activated c-Ha-ras gene and transforms rat-1a cells as a single gene. Proc Natl Acad Sci U S A. 1989, 86 (7): 2257-2261. 10.1073/pnas.86.7.2257.CrossRefPubMedPubMedCentral
19.
Domann FE, Levy JP, Birrer MJ, Bowden GT: Stable expression of a c-JUN deletion mutant in two malignant mouse epidermal cell lines blocks tumor formation in nude mice. Cell Growth Differ. 1994, 5 (1): 9-16.PubMed
20.
Dong Z, Crawford HC, Lavrovsky V, Taub D, Watts R, Matrisian LM, Colburn NH: A dominant negative mutant of jun blocking 12-O-tetradecanoylphorbol-13-acetate-induced invasion in mouse keratinocytes. Mol Carcinog. 1997, 19 (3): 204-212. 10.1002/(SICI)1098-2744(199707)19:3<204::AID-MC8>3.0.CO;2-D.CrossRefPubMed
21.
Stepniak E, Ricci R, Eferl R, Sumara G, Sumara I, Rath M, Hui L, Wagner EF: c-Jun/AP-1 controls liver regeneration by repressing p53/p21 and p38 MAPK activity. Genes Dev. 2006, 20 (16): 2306-2314. 10.1101/gad.390506.CrossRefPubMedPubMedCentral
22.
Liu Y, Lu C, Shen Q, Munoz-Medellin D, Kim H, Brown PH: AP-1 blockade in breast cancer cells causes cell cycle arrest by suppressing G1 cyclin expression and reducing cyclin-dependent kinase activity. Oncogene. 2004, 23 (50): 8238-8246. 10.1038/sj.onc.1207889.CrossRefPubMed
23.
24.
Ozanne BW, McGarry L, Spence HJ, Johnston I, Winnie J, Meagher L, Stapleton G: Transcriptional regulation of cell invasion: AP-1 regulation of a multigenic invasion programme. Eur J Cancer. 2000, 36 (13 Spec No): 1640-1648. 10.1016/S0959-8049(00)00175-1.CrossRefPubMed
25.
Smith LM, Wise SC, Hendricks DT, Sabichi AL, Bos T, Reddy P, Brown PH, Birrer MJ: cJun overexpression in MCF-7 breast cancer cells produces a tumorigenic, invasive and hormone resistant phenotype. Oncogene. 1999, 18 (44): 6063-6070. 10.1038/sj.onc.1202989.CrossRefPubMed
26.
Bos TJ, Margiotta P, Bush L, Wasilenko W: Enhanced cell motility and invasion of chicken embryo fibroblasts in response to Jun over-expression. Int J Cancer. 1999, 81 (3): 404-410. 10.1002/(SICI)1097-0215(19990505)81:3<404::AID-IJC14>3.0.CO;2-I.CrossRefPubMed
27.
Zajchowski DA, Bartholdi MF, Gong Y, Webster L, Liu HL, Munishkin A, Beauheim C, Harvey S, Ethier SP, Johnson PH: Identification of gene expression profiles that predict the aggressive behavior of breast cancer cells. Cancer Res. 2001, 61 (13): 5168-5178.PubMed
28.
Malliri A, Symons M, Hennigan RF, Hurlstone AF, Lamb RF, Wheeler T, Ozanne BW: The transcription factor AP-1 is required for EGF-induced activation of rho-like GTPases, cytoskeletal rearrangements, motility, and in vitro invasion of A431 cells. J Cell Biol. 1998, 143 (4): 1087-1099. 10.1083/jcb.143.4.1087.CrossRefPubMedPubMedCentral
29.
Lester BR, McCarthy JB: Tumor cell adhesion to the extracellular matrix and signal transduction mechanisms implicated in tumor cell motility, invasion and metastasis. Cancer Metastasis Rev. 1992, 11 (1): 31-44. 10.1007/BF00047601.CrossRefPubMed
30.
Kovary K, Bravo R: The jun and fos protein families are both required for cell cycle progression in fibroblasts. Mol Cell Biol. 1991, 11 (9): 4466-4472.CrossRefPubMedPubMedCentral
31.
Smith MJ, Prochownik EV: Inhibition of c-jun causes reversible proliferative arrest and withdrawal from the cell cycle. Blood. 1992, 79 (8): 2107-2115.PubMed
32.
Rinehart-Kim J, Johnston M, Birrer M, Bos T: Alterations in the gene expression profile of MCF-7 breast tumor cells in response to c-Jun. Int J Cancer. 2000, 88 (2): 180-190. 10.1002/1097-0215(20001015)88:2<180::AID-IJC6>3.0.CO;2-H.CrossRefPubMed
33.
Briggs J, Chamboredon S, Castellazzi M, Kerry JA, Bos TJ: Transcriptional upregulation of SPARC, in response to c-Jun overexpression, contributes to increased motility and invasion of MCF7 breast cancer cells. Oncogene. 2002, 21 (46): 7077-7091. 10.1038/sj.onc.1205857.CrossRefPubMed
34.
Crowe DL, Tsang KJ, Shemirani B: Jun N-terminal kinase 1 mediates transcriptional induction of matrix metalloproteinase 9 expression. Neoplasia. 2001, 3 (1): 27-32. 10.1038/sj.neo.7900135.CrossRefPubMedPubMedCentral
35.
Vleugel MM, Greijer AE, Bos R, van der Wall E, van Diest PJ: c-Jun activation is associated with proliferation and angiogenesis in invasive breast cancer. Hum Pathol. 2006, 37 (6): 668-674. 10.1016/j.humpath.2006.01.022.CrossRefPubMed
Metadata
Title
Critical role of c-Jun overexpression in liver metastasis of human breast cancer xenograft model
Authors
Yan Zhang
Xiaoyun Pu
Ming Shi
Liyong Chen
Yuhua Song
Lu Qian
Guogang Yuan
Hao Zhang
Ming Yu
Meiru Hu
Beifen Shen
Ning Guo
Publication date
01-12-2007
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2007
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-7-145

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