Skip to main content
SpringerLink
Log in

Altered Rho GTPase Signaling Pathways in Breast Cancer Cells

  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

The Rho family of GTPases have emerged as key players in regulating a diverse set of biological activities including actin organization, focal complex/adhesion assembly, cell motility, cell polarity, gene transcription and cell-cycle progression. Some Rho GTPases and their signaling components are overexpressed and/or are hyperactive in breast cancer and recent studies have shown a requirement for Rho GTPases in breast cancer cell metastasis in vivo. Herein we describe the contribution of Rho GTPase to the malignant phenotype of breast cancer cells and the role of these pathways as potential targets for breast cancer therapy. Rho GTPases promote cell-cycle progression through cyclin D1, and cyclin D1 in turn reduces cellular adhesion and promotes migration, an example of ‘inside-out’ signaling by cyclin D1. As cyclin D1 overexpression correlates with metastatic cancer, the ‘inside-out’ signaling function of cyclin D1 to promote cell migration may represent a useful new therapeutic target.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Hall A: Rho GTPases and the actin cytoskeleton. Science 279: 509–514, 1998

    Google Scholar 

  2. Ridley AJ, Paterson HF, Johnston CL, Diekmann D, Hall A: The small GTP-binding protein rac regulates growth factorinduced membrane ruffling. Cell 70: 401–410, 1992

    Google Scholar 

  3. Ridley AJ, Hall A: The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell 70: 389–399, 1992

    Google Scholar 

  4. Bishop AL, Hall A: Rho GTPases and their effector proteins. Biochem J 348(Pt 2): 241–255, 2000

    Google Scholar 

  5. Olofsson B: Rho guanine dissociation inhibitors: pivotal molecules in cellular signalling. Cell Signal 11: 545–554, 1999

    Google Scholar 

  6. Whitehead IP, Campbell S, Rossman KL, Der CJ: Dbl family proteins. Biochim Biophys Acta 1332: F1-F23, 1997

    Google Scholar 

  7. Zheng Y: Dbl family guanine nucleotide exchange factors. Trends Biochem Sci 26: 724–732, 2001

    Google Scholar 

  8. Peck J, Douglas IV G, Wu CH, Burbelo PD: Human RhoGAP domain-containing proteins: structure, function and evolutionary relationships. FEBS Lett 528: 27–34, 2002

    Google Scholar 

  9. Fritz G, Brachetti C, Bahlmann F, Schmidt M, Kaina B: Rho GTPases in human breast tumours: expression and mutation analyses and correlation with clinical parameters. Br J Cancer 87: 635–644, 2002

    Google Scholar 

  10. Fritz G, Just I, Kaina B: Rho GTPases are over-expressed in human tumors. Int J Cancer 81: 682–687, 1999

    Google Scholar 

  11. van Golen KL, Davies S, Wu ZF, Wang Y, Bucana CD, Root H, Chandrasekharappa S, Strawderman M, Ethier SP, Merajver SD: A novel putative low-affinity insulin-like growth factorbinding protein, LIBC (lost in inflammatory breast cancer), and RhoC GTPase correlate with the inflammatory breast cancer phenotype. Clin Cancer Res 5: 2511–2519, 1999

    Google Scholar 

  12. Kleer CG, van Golen KL, Zhang Y, Wu ZF, Rubin MA, Merajver SD: Characterization of RhoC expression in benign and malignant breast disease: a potential new marker for small breast carcinomas with metastatic ability. Am J Pathol 160: 579–584, 2002

    Google Scholar 

  13. Clark EA, Golub TR, Lander ES, Hynes RO: Genomic analysis of metastasis reveals an essential role for RhoC. Nature 406: 532–535, 2000

    Google Scholar 

  14. Schnelzer A, Prechtel D, Knaus U, Dehne K, Gerhard M, Graeff H, Harbeck N, Schmitt M, Lengyel E: Rac1 in human breast cancer; overexpression, mutation analysis, and characterization of a new isoform, Rac1b. Oncogene 19: 3013–3020, 2000

    Google Scholar 

  15. Mira JP, Benard V, Groffen J, Sanders LC, Knaus UG: Endogenous, hyperactive Rac3 controls proliferation of breast cancer cells by a p21-activated kinase-dependent pathway. Proc Natl Acad Sci USA 97: 185–189, 2000

    Google Scholar 

  16. Evers EE, Zondag GCM, Malliri A, Price LS, ten Klooster J-P, van der Kammen RA, Collard JG: Rho family of proteins in cell adhesion and cell migration. Eur J Cancer 36: 1269–1274, 2000

    Google Scholar 

  17. Keely PJ, Westwick JK, Whitehead IP, Der CJ, Parise LV: Cdc42 and Rac1 induce integrin-mediated cell motility and invasiveness through PI(3)K. Nature 390: 632–636, 1997

    Google Scholar 

  18. van Golen KL, Bao LW, Pan Q, Miller FR, Wu ZF, Merajver SD: Mitogen activated protein kinase pathway is involved in RhoC GTPase induced motility, invasion and angiogenesis in inflammatory breast cancer. Clin Exp Metast 19: 301–311, 2002

    Google Scholar 

  19. van Golen KL, Wu ZF, Qiao XT, Bao L, Merajver SD: RhoC GTPase overexpression modulates induction of angiogenic factors in breast cells. Neoplasia 2: 418–425, 2000

    Google Scholar 

  20. Bouzahzah B, Albanese C, Ahmed F, Pixley F, Lisanti MP, Segall JD, Condeelis J, Joyce D, Minden A, Der CJ, Chan A, Symons M, Pestell RG: Rho family GTPases regulate mammary epithelium cell growth and metastasis through distinguishable pathways. Mol Med 7: 816–830, 2001

    Google Scholar 

  21. Olson MF, Ashworth A, Hall A: An essential role for Rho, Rac and Cdc42 GTPases in cell cycle progression through G1. Science 269: 1270–1272, 1995

    Google Scholar 

  22. Qiu R-G, Chen J, McCormick F, Symons M: A role for Rho in Ras transformation. Proc Natl Acad Sci USA 92: 11781–11785, 1995

    Google Scholar 

  23. Westwick JK, Lambert QT, Clark GJ, Symons M, Van Aelst L, Pestell RG, Der CJ: Rac regulation of transformation, gene expression and actin organisation by multiple, PAKindependent pathways. Mol Cell Biol 17: 1324–1335, 1997

    Google Scholar 

  24. Westwick JK, Lee RJ, Lambert QT, Symons M, Pestell RG, Der CJ, Whitehead IP: Transforming potential of Dbl family proteins correlates with transcription from the cyclin D1 promoter but not with activation of Jun NH2-terminal kinase, p38/Mpk2, serum response factor, or c-Jun. J Biol Chem 273: 16739–16747, 1998

    Google Scholar 

  25. Whitehead IP, Lambert QT, Glaven JA, Abe K, Rossman KL, Mahon GM, Trzaskos JM, Kay R, Campbell SL, Der CJ: Dependence of Dbl and Dbs transformation on MEK and NF-κ activation. Mol Cell Biol 19: 7759–7770, 1999

    Google Scholar 

  26. Liberto M, Cobrinik D, Minden A: Rho regulates p21(CIP1), cyclin D1, and checkpoint control inmammary epithelial cells. Oncogene 21: 1590–1599, 2002

    Google Scholar 

  27. Lee RJ, Albanese C, Fu M, D'Amico M, Lin B, Watanabe G, Haines GKI, Siegel PM, Hung MC, Yarden Y, Horowitz JM, Muller WJ, Pestell RG: Cyclin D1 is required for transformation by activated Neu and is induced through an E2Fdependent signaling pathway. Mol Cell Biol 20: 672–683, 2000

    Google Scholar 

  28. Joyce D, Bouzahzah B, Fu M, Albanese C, D'Amico M, Steer J, Klein JU, Lee RJ, Segall JE, Westwick JK, Der CJ, Pestell RG: Integration of Rac-dependent regulation of cyclin D1 transcription through an NF-κ-dependent pathway. J Biol Chem 274: 25245–25249, 1999

    Google Scholar 

  29. Albanese C, Jarrett CR, Joyce D, Hughes J, Wu K, D'Amico M, Fu M, Sakamaki T, Ben Ze'ev A, Lamberti C, Lin K-M, Gaynor RB, Byers SW, Pestell RG: IKKá activates Tcf signaling and cyclin D1 gene expression through phosphorylation of β-catenin. Mol Cell Biol (in press)

  30. Guttridge DC, Albanese C, Reuther JY, Pestell RG, Baldwin AS: NF-κ controls cell growth and differentiation through the transcriptional regulation of cyclin D1. Mol Cell Biol 19: 5785–5799, 1999

    Google Scholar 

  31. Salh B, Marotta A, Wagey R, Sayed M, Pelech S: Dysregulation of phosphatidylinositol 3-kinase and downstream effectors in human breast cancer. Int J Cancer 98: 148–154, 2002

    Google Scholar 

  32. Vadlamudi RK, Adam L, Wang RA, Mandal M, Nguyen D, Sahin A, Chernoff J, Hung MC, Kumar R: Regulatable expression of p21-activated kinase-1 promotes anchorageindependent growth and abnormal organization of mitotic spindles in human epithelial breast cancer cells. J Biol Chem 275: 36238–36244, 2000

    Google Scholar 

  33. Adam L, Vadlamudi R, Kondapaka SB, Chernoff J, Mendelsohn J, Kumar R: Heregulin regulates cytoskeletal reorganization and cell migration through the p21-activated kinase-1 via phosphatidylinositol-3 kinase. J Biol Chem 273: 28238–28246, 1998

    Google Scholar 

  34. Adam L, Vadlamudi R, Mandal M, Chernoff J, Kumar R: Regulation of microfilament reorganization and invasiveness of breast cancer cells by kinase dead p21-activated kinase-1. J Biol Chem 275: 12041–12050, 2000

    Google Scholar 

  35. Uruno T, Liu J, Zhang P, Fan YX, Egile C, Li R, Mueller SC, Zhan X: Activation of Arp2/3 complex-mediated actin polymerization by cortactin. Nat Cell Biol 3: 259–266, 2001

    Google Scholar 

  36. Itoh K, Yoshioka K, Akedo H, Uehata M, Ishizaki T, Narumiya S: An essential part for Rho-associated kinase in the transcellular invasion of tumor cells. Nat Med 5: 221–225, 1999

    Google Scholar 

  37. Yoshioka K, Nakamori S, Itoh K: Overexpression of small GTP-binding protein RhoA promotes invasion of tumor cells. Cancer Res 59: 2004–2010, 1999

    Google Scholar 

  38. Nguyen QD, Faivre S, Bruyneel E, Rivat C, Seto M, Endo T, Mareel M, Emami S, Gespach C: RhoA-and RhoDdependent regulatory switch of Galpha subunit signaling by PAR-1 receptors in cellular invasion. Faseb J 16: 565–576, 2002

    Google Scholar 

  39. Sahai E, Marshall CJ: ROCK and Dia have opposing effects on adherens junctions downstream of Rho. Nat Cell Biol 4: 408–415, 2002

    Google Scholar 

  40. Prendergast GC: ‘Actin’ up: RhoB in cancer and apoptosis. Nat Rev Cancer 1: 162–168, 2001

    Google Scholar 

  41. Du W, Prendergast GC: Geranylgeranylated RhoB mediates suppression of human tumor cell growth by farnesyltransferase inhibitors. Cancer Res 59: 5492–5496, 1999

    Google Scholar 

  42. Denoyelle C, Vasse M, Korner M, Mishal Z, Ganne F, Vannier JP, Soria J, Soria C: Cerivastatin, an inhibitor of HMGCoA reductase, inhibits the signaling pathways involved in the invasiveness and metastatic properties of highly invasive breast cancer cell lines: an in vitro study. Carcinogenesis 22: 1139–1148, 2001

    Google Scholar 

  43. Nheu TV, He H, Hirokawa Y, Tamaki K, Florin L, Schmitz ML, Suzuki-Takahashi I, Jorissen RN, Burgess AW, Nishimura S, Wood J, Maruta H: The K252a derivatives, inhibitors for the PAK/MLK kinase family selectively block the growth of RAS transformants. Cancer J 8: 328–336, 2002

    Google Scholar 

  44. Hendrik Gille H, Downward J: Multiple ras effector pathways contribute to G1 cell cycle progression. J Biol Chem 274: 22033–22040, 1999

    Google Scholar 

  45. Holnthoner W, Pillinger M, Groger M, Wolff K, Ashton AW, Albanese C, Neumeister P, Pestell RG, Petzelbauer P: Fibroblast growth factor-2 induces Lef/Tcf-dependent transcription in human endothelial cells. J Biol Chem 277: 45847–45853, 2002

    Google Scholar 

  46. Neumeister P, Pixley FJ, Xiong Y, Xie H, Wu K, Ashton A, Cammer M, Chan A, Symons M, Stanley ER, Pestell RG: Cyclin D1 governs adhesion and motility of macrophages. Mol Biol Cell 14: 2005–2015, 2003

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA

    Peter Burbelo, Anton Wellstein & Richard G. Pestell

Authors
  1. Peter Burbelo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anton Wellstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Richard G. Pestell
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Burbelo, P., Wellstein, A. & Pestell, R.G. Altered Rho GTPase Signaling Pathways in Breast Cancer Cells. Breast Cancer Res Treat 84, 43–48 (2004). https://doi.org/10.1023/B:BREA.0000018422.02237.f9

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:BREA.0000018422.02237.f9

Search

Navigation