Mammary Epithelial-specific Disruption of the Focal Adhesion Kinase Blocks Mammary Tumor Progression

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2007 Dec 7

PMID 18056629

Citations 125

Authors

Hicham Lahlou

Virginie Sanguin-Gendreau

Dongmei Zuo

Robert D Cardiff

Gordon W McLean

Margaret C Frame

William J Muller

Affiliations

Soon will be listed here.

Abstract

Elevated expression and activation of the focal adhesion kinase (FAK) occurs in a large proportion of human breast cancers. Although several studies have implicated FAK as an important signaling molecule in cell culture systems, evidence supporting a role for FAK in mammary tumor progression is lacking. To directly assess the role of FAK in this process, we have used the Cre/loxP recombination system to disrupt FAK function in the mammary epithelium of a transgenic model of breast cancer. Using this approach, we demonstrate that FAK expression is required for the transition of premalignant hyperplasias to carcinomas and their subsequent metastases. This dramatic block in tumor progression was further correlated with impaired mammary epithelial proliferation. These observations provide direct evidence that FAK plays a critical role in mammary tumor progression.

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References

White D, Kurpios N, Zuo D, Hassell J, Blaess S, Mueller U . Targeted disruption of beta1-integrin in a transgenic mouse model of human breast cancer reveals an essential role in mammary tumor induction. Cancer Cell. 2004; 6(2):159-70. DOI: 10.1016/j.ccr.2004.06.025. View

Mitra S, Hanson D, Schlaepfer D . Focal adhesion kinase: in command and control of cell motility. Nat Rev Mol Cell Biol. 2005; 6(1):56-68. DOI: 10.1038/nrm1549. View

Li N, Zhang Y, Naylor M, Schatzmann F, Maurer F, Wintermantel T . Beta1 integrins regulate mammary gland proliferation and maintain the integrity of mammary alveoli. EMBO J. 2005; 24(11):1942-53. PMC: 1142608. DOI: 10.1038/sj.emboj.7600674. View

Nagy T, Wei H, Shen T, Peng X, Liang C, Gan B . Mammary epithelial-specific deletion of the focal adhesion kinase gene leads to severe lobulo-alveolar hypoplasia and secretory immaturity of the murine mammary gland. J Biol Chem. 2007; 282(43):31766-76. DOI: 10.1074/jbc.M705403200. View

Slack-Davis J, Martin K, Tilghman R, Iwanicki M, Ung E, Autry C . Cellular characterization of a novel focal adhesion kinase inhibitor. J Biol Chem. 2007; 282(20):14845-52. DOI: 10.1074/jbc.M606695200. View

Mitra S, Lim S, Chi A, Schlaepfer D . Intrinsic focal adhesion kinase activity controls orthotopic breast carcinoma metastasis via the regulation of urokinase plasminogen activator expression in a syngeneic tumor model. Oncogene. 2006; 25(32):4429-40. DOI: 10.1038/sj.onc.1209482. View

Hannigan G, Troussard A, Dedhar S . Integrin-linked kinase: a cancer therapeutic target unique among its ILK. Nat Rev Cancer. 2005; 5(1):51-63. DOI: 10.1038/nrc1524. View

Lark A, Livasy C, Dressler L, Moore D, Millikan R, Geradts J . High focal adhesion kinase expression in invasive breast carcinomas is associated with an aggressive phenotype. Mod Pathol. 2005; 18(10):1289-94. DOI: 10.1038/modpathol.3800424. View

Ignatoski K, Ethier S . Constitutive activation of pp125fak in newly isolated human breast cancer cell lines. Breast Cancer Res Treat. 1999; 54(2):173-82. DOI: 10.1023/a:1006135331912. View

10.

Aguirre Ghiso J . Inhibition of FAK signaling activated by urokinase receptor induces dormancy in human carcinoma cells in vivo. Oncogene. 2002; 21(16):2513-24. DOI: 10.1038/sj.onc.1205342. View

11.

Guo W, Giancotti F . Integrin signalling during tumour progression. Nat Rev Mol Cell Biol. 2004; 5(10):816-26. DOI: 10.1038/nrm1490. View

12.

Kawamoto S, Niwa H, Tashiro F, Sano S, Kondoh G, Takeda J . A novel reporter mouse strain that expresses enhanced green fluorescent protein upon Cre-mediated recombination. FEBS Lett. 2000; 470(3):263-8. DOI: 10.1016/s0014-5793(00)01338-7. View

13.

Duxbury M, Ito H, Zinner M, Ashley S, Whang E . Focal adhesion kinase gene silencing promotes anoikis and suppresses metastasis of human pancreatic adenocarcinoma cells. Surgery. 2004; 135(5):555-62. DOI: 10.1016/j.surg.2003.10.017. View

14.

Madan R, Smolkin M, Cocker R, Fayyad R, Oktay M . Focal adhesion proteins as markers of malignant transformation and prognostic indicators in breast carcinoma. Hum Pathol. 2005; 37(1):9-15. DOI: 10.1016/j.humpath.2005.09.024. View

15.

Guy C, Cardiff R, Muller W . Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol Cell Biol. 1992; 12(3):954-61. PMC: 369527. DOI: 10.1128/mcb.12.3.954-961.1992. View

16.

Liu T, Lafortune T, Honda T, Ohmori O, Hatakeyama S, Meyer T . Inhibition of both focal adhesion kinase and insulin-like growth factor-I receptor kinase suppresses glioma proliferation in vitro and in vivo. Mol Cancer Ther. 2007; 6(4):1357-67. DOI: 10.1158/1535-7163.MCT-06-0476. View

17.

Ahmed F, Wyckoff J, Lin E, Wang W, Wang Y, Hennighausen L . GFP expression in the mammary gland for imaging of mammary tumor cells in transgenic mice. Cancer Res. 2002; 62(24):7166-9. View

18.

Andrechek E, White D, Muller W . Targeted disruption of ErbB2/Neu in the mammary epithelium results in impaired ductal outgrowth. Oncogene. 2004; 24(5):932-7. DOI: 10.1038/sj.onc.1208230. View

19.

Xu L, Yang X, Bradham C, Brenner D, Baldwin Jr A, Craven R . The focal adhesion kinase suppresses transformation-associated, anchorage-independent apoptosis in human breast cancer cells. Involvement of death receptor-related signaling pathways. J Biol Chem. 2000; 275(39):30597-604. DOI: 10.1074/jbc.M910027199. View

20.

Johnson F, Saigal B, Talpaz M, Donato N . Dasatinib (BMS-354825) tyrosine kinase inhibitor suppresses invasion and induces cell cycle arrest and apoptosis of head and neck squamous cell carcinoma and non-small cell lung cancer cells. Clin Cancer Res. 2005; 11(19 Pt 1):6924-32. DOI: 10.1158/1078-0432.CCR-05-0757. View