HER2/ErbB2-induced Breast Cancer Cell Migration and Invasion Require P120 Catenin Activation of Rac1 and Cdc42

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2010 Jul 3

PMID 20595387

Citations 53

Authors

Emhonta Johnson

Darcie D Seachrist

Carlos M DeLeon-Rodriguez

Kristen L Lozada

John Miedler

Fadi W Abdul-Karim

Ruth A Keri

Affiliations

Soon will be listed here.

Abstract

Breast cancers that overexpress the receptor tyrosine kinase ErbB2/HER2/Neu result in poor patient outcome because of extensive metastatic progression. Herein, we delineate a molecular mechanism that may govern this malignant phenotype. ErbB2 induction of migration requires activation of the small GTPases Rac1 and Cdc42. The ability of ErbB2 to activate these small GTPases necessitated expression of p120 catenin, which is itself up-regulated by signaling through ErbB2 and the tyrosine kinase Src. Silencing p120 in ErbB2-dependent breast cancer cell lines dramatically inhibited migration and invasion as well as activation of Rac1 and Cdc42. In contrast, overexpression of constitutively active mutants of these GTPases reversed the effects of p120 silencing. Lastly, ectopic expression of p120 promoted migration and invasion and potentiated metastatic progression of a weakly metastatic, ErbB2-dependent breast cancer cell line. These results suggest that p120 acts as an obligate intermediate between ErbB2 and Rac1/Cdc42 to modulate the metastatic potential of breast cancer cells.

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References

Karayiannakis A, Syrigos K, Alexiou D, Kalahanis N, Rosenberg T, Bastounis E . Expression patterns of the novel catenin p120cas in gastrointestinal cancers. Anticancer Res. 2000; 19(5C):4401-5. View

Aho S, Levansuo L, Montonen O, Kari C, Rodeck U, Uitto J . Specific sequences in p120ctn determine subcellular distribution of its multiple isoforms involved in cellular adhesion of normal and malignant epithelial cells. J Cell Sci. 2002; 115(Pt 7):1391-402. DOI: 10.1242/jcs.115.7.1391. View

Liu Y, Li Q, Miao Y, Xu H, Dai S, Wei Q . Ablation of p120-catenin enhances invasion and metastasis of human lung cancer cells. Cancer Sci. 2009; 100(3):441-8. PMC: 11158803. DOI: 10.1111/j.1349-7006.2008.01067.x. View

Ishizawar R, Miyake T, Parsons S . c-Src modulates ErbB2 and ErbB3 heterocomplex formation and function. Oncogene. 2006; 26(24):3503-10. DOI: 10.1038/sj.onc.1210138. View

Yang C, Liu Y, Lemmon M, Kazanietz M . Essential role for Rac in heregulin beta1 mitogenic signaling: a mechanism that involves epidermal growth factor receptor and is independent of ErbB4. Mol Cell Biol. 2006; 26(3):831-42. PMC: 1347034. DOI: 10.1128/MCB.26.3.831-842.2006. View

Seton-Rogers S, Lu Y, Hines L, Koundinya M, LaBaer J, Muthuswamy S . Cooperation of the ErbB2 receptor and transforming growth factor beta in induction of migration and invasion in mammary epithelial cells. Proc Natl Acad Sci U S A. 2004; 101(5):1257-62. PMC: 337040. DOI: 10.1073/pnas.0308090100. View

Yanagisawa M, Huveldt D, Kreinest P, Lohse C, Cheville J, Parker A . A p120 catenin isoform switch affects Rho activity, induces tumor cell invasion, and predicts metastatic disease. J Biol Chem. 2008; 283(26):18344-54. PMC: 2440599. DOI: 10.1074/jbc.M801192200. View

Mastracci T, Tjan S, Bane A, OMalley F, Andrulis I . E-cadherin alterations in atypical lobular hyperplasia and lobular carcinoma in situ of the breast. Mod Pathol. 2005; 18(6):741-51. DOI: 10.1038/modpathol.3800362. View

Qiao M, Iglehart J, Pardee A . Metastatic potential of 21T human breast cancer cells depends on Akt/protein kinase B activation. Cancer Res. 2007; 67(11):5293-9. DOI: 10.1158/0008-5472.CAN-07-0877. View

10.

Bellovin D, Bates R, Muzikansky A, Rimm D, Mercurio A . Altered localization of p120 catenin during epithelial to mesenchymal transition of colon carcinoma is prognostic for aggressive disease. Cancer Res. 2005; 65(23):10938-45. DOI: 10.1158/0008-5472.CAN-05-1947. View

11.

Reynolds A, Daniel J, McCrea P, Wheelock M, Wu J, Zhang Z . Identification of a new catenin: the tyrosine kinase substrate p120cas associates with E-cadherin complexes. Mol Cell Biol. 1994; 14(12):8333-42. PMC: 359372. DOI: 10.1128/mcb.14.12.8333-8342.1994. View

12.

Shibata T, Kokubu A, Sekine S, Kanai Y, Hirohashi S . Cytoplasmic p120ctn regulates the invasive phenotypes of E-cadherin-deficient breast cancer. Am J Pathol. 2004; 164(6):2269-78. PMC: 1615772. DOI: 10.1016/S0002-9440(10)63783-2. View

13.

Wildenberg G, Dohn M, Carnahan R, Davis M, Lobdell N, Settleman J . p120-catenin and p190RhoGAP regulate cell-cell adhesion by coordinating antagonism between Rac and Rho. Cell. 2006; 127(5):1027-39. DOI: 10.1016/j.cell.2006.09.046. View

14.

Landis M, Seachrist D, Montanez-Wiscovich M, Danielpour D, Keri R . Gene expression profiling of cancer progression reveals intrinsic regulation of transforming growth factor-beta signaling in ErbB2/Neu-induced tumors from transgenic mice. Oncogene. 2005; 24(33):5173-90. PMC: 1431507. DOI: 10.1038/sj.onc.1208712. View

15.

Bremnes R, Veve R, Hirsch F, Franklin W . The E-cadherin cell-cell adhesion complex and lung cancer invasion, metastasis, and prognosis. Lung Cancer. 2002; 36(2):115-24. DOI: 10.1016/s0169-5002(01)00471-8. View

16.

Sorlie T, Tibshirani R, Parker J, Hastie T, Marron J, Nobel A . Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A. 2003; 100(14):8418-23. PMC: 166244. DOI: 10.1073/pnas.0932692100. View

17.

Moghal N, Sternberg P . Multiple positive and negative regulators of signaling by the EGF-receptor. Curr Opin Cell Biol. 1999; 11(2):190-6. DOI: 10.1016/s0955-0674(99)80025-8. View

18.

Moasser M . The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene. 2007; 26(45):6469-87. PMC: 3021475. DOI: 10.1038/sj.onc.1210477. View

19.

Macpherson I, Hooper S, Serrels A, McGarry L, Ozanne B, Harrington K . p120-catenin is required for the collective invasion of squamous cell carcinoma cells via a phosphorylation-independent mechanism. Oncogene. 2007; 26(36):5214-28. DOI: 10.1038/sj.onc.1210334. View

20.

Guy C, Webster M, Schaller M, Parsons T, Cardiff R, Muller W . Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. Proc Natl Acad Sci U S A. 1992; 89(22):10578-82. PMC: 50384. DOI: 10.1073/pnas.89.22.10578. View