Tumor Biology

, Volume 33, Issue 5, pp 1581–1587 | Cite as

Increased expression of Rab25 in breast cancer correlates with lymphatic metastasis

  • Y. X. Yin
  • F. Shen
  • H. Pei
  • Y. Ding
  • Hua Zhao
  • Min Zhao
  • Q. Chen
Research Article

Abstract

Breast cancer is the most common cancer in women worldwide. Studies have suggested that Ras-related protein 25 (Rab25), a member of Rab small GTPase family, is involved in the pathogenesis of breast cancer. In this study, we investigated whether the expression of Rab25 correlated with lymphatic metastasis in breast cancer and whether the expression of Rab25 was positively correlated with oestrogen receptor (ER) and progesterone receptor (PR) expression in breast cancer. Breast cancer tissues from 42 invasive ductal breast cancer patients with or without lymphatic metastasis were collected and the levels of Rab25 mRNA and protein measured by quantitative real-time PCR and immunohistochemistry, respectively. The mRNA level of Rab25 was significantly increased in invasive ductal breast cancer with lymphatic metastasis compared to that in invasive ductal breast cancer without lymphatic metastasis. Immunohistochemical analysis demonstrated that Rab25 and vascular endothelial growth factor (VEGF) were highly expressed in invasive ductal breast cancer with lymphatic metastasis regardless of whether the cancer is ER and PR positive or negative. Higher expression of Rab25 positively correlated with VEGF expression. However, the expressions of Rab25 in ER and PR-positive cancers were much higher than ER and PR-negative cancers regardless of whether lymphatic metastasis occurred. These data suggest that higher level of Rab25 was associated with lymphatic metastasis, specifically in ER and PR-positive breast cancer. The better understanding of the mechanism of Rab25 may provide a basis for the development of a novel therapeutic target in breast cancer.

Keywords

Rab25 Breast cancer Lymphatic metastasis Oestrogen receptor Progesterone receptor 

Notes

Acknowledgments

This study was supported by the Chinese National Nature Sciences Foundation (grant number 81100437). The authors thank all the women who donated the tissues for this study. The authors would like to thank Dr. Joanna James, The University of Auckland, New Zealand for reviewing this manuscript.

Conflicts of interest

None

References

  1. 1.
    Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.CrossRefPubMedGoogle Scholar
  2. 2.
    Gonzalez-Angulo AM, Morales-Vasquez F, Hortobagyi GN. Overview of resistance to systemic therapy in patients with breast cancer. Adv Exp Med Biol. 2007;608:1–22.CrossRefPubMedGoogle Scholar
  3. 3.
    Goldenring JR, Shen KR, Vaughan HD, Modlin IM. Identification of a small GTP-binding protein, Rab25, expressed in the gastrointestinal mucosa, kidney, and lung. J Biol Chem. 1993;268:18419–22.PubMedGoogle Scholar
  4. 4.
    Schwartz SL, Cao C, Pylypenko O, Rak A, Wandinger-Ness A. Rab GTPases at a glance. J Cell Sci. 2007;120:3905–10.CrossRefPubMedGoogle Scholar
  5. 5.
    He H, Dai F, Yu L, She X, Zhao Y, Jiang J, Chen X, Zhao S. Identification and characterization of nine novel human small GTPases showing variable expressions in liver cancer tissues. Gene Expr. 2002;10:231–42.CrossRefPubMedGoogle Scholar
  6. 6.
    Mor O, Nativ O, Stein A, Novak L, Lehavi D, Shiboleth Y, Rozen A, Berent E, Brodsky L, Feinstein E, Rahav A, Morag K, Rothenstein D, Persi N, Mor Y, Skaliter R, Regev A. Molecular analysis of transitional cell carcinoma using cDNA microarray. Oncogene. 2003;22:7702–10.CrossRefPubMedGoogle Scholar
  7. 7.
    Caswell PT, Spence HJ, Parsons M, White DP, Clark K, Cheng KW, Mills GB, Humphries MJ, Messent AJ, Anderson KI, McCaffrey MW, Ozanne BW, Norman JC. Rab25 associates with alpha5beta1 integrin to promote invasive migration in 3D microenvironments. Dev Cell. 2007;13:496–510.CrossRefPubMedGoogle Scholar
  8. 8.
    Cheng KW, Lahad JP, Kuo WL, Lapuk A, Yamada K, Auersperg N, Liu J, Smith-McCune K, Lu KH, Fishman D, Gray JW, Mills GB. The RAB25 small GTPase determines aggressiveness of ovarian and breast cancers. Nat Med. 2004;10:1251–6.CrossRefPubMedGoogle Scholar
  9. 9.
    Cheng JM, Ding M, Aribi A, Shah P, Rao K. Loss of RAB25 expression in breast cancer. Int J Cancer. 2006;118:2957–64.CrossRefPubMedGoogle Scholar
  10. 10.
    Fan Y, Xin XY, Chen BL, Ma XD. Knockdown of Rab25 expression by RNAi inhibits growth of human epithelial ovarian cancer cells in vitro and in vivo. Pathology. 2006;38:561–7.CrossRefPubMedGoogle Scholar
  11. 11.
    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.CrossRefPubMedGoogle Scholar
  12. 12.
    Cheng JM, Volk L, Janaki DK, Vyakaranam S, Ran S, Rao KA. Tumor suppressor function of Rab25 in triple-negative breast cancer. Int J Cancer. 2010;126:2799–812.PubMedGoogle Scholar
  13. 13.
    Jones MC, Caswell PT, Norman JC. Endocytic recycling pathways: emerging regulators of cell migration. Curr Opin Cell Biol. 2006;18:549–57.CrossRefPubMedGoogle Scholar
  14. 14.
    Li X, Lim B. RhoGTPases and their role in cancer. Oncol Res. 2003;13:323–31.PubMedGoogle Scholar
  15. 15.
    Hammond ME, Hayes DF, Wolff AC, Mangu PB, Temin S. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Oncol Pract. 2010;6:195–7.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Bonanomi A, Kojic D, Giger B, Rickenbach Z, Jean-Richard-Dit-Bressel L, Berger C, Niggli FK, Nadal D. Quantitative cytokine gene expression in human tonsils at excision and during histoculture assessed by standardized and calibrated real-time PCR and novel data processing. J Immunol Methods. 2003;283:27–43.CrossRefPubMedGoogle Scholar
  17. 17.
    Soslow RA, Dannenberg AJ, Rush D, Woerner BM, Khan KN, Masferrer J, Koki AT. COX-2 is expressed in human pulmonary, colonic, and mammary tumors. Cancer. 2000;89:2637–45.CrossRefPubMedGoogle Scholar
  18. 18.
    Society AC. "Cancer Facts and Figures," Atlanta, GA, 2010.Google Scholar
  19. 19.
    Goldenring JR, Nam KT. Rab25 as a tumour suppressor in colon carcinogenesis. Br J Cancer. 2011;104:33–6.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Wang W, Wyckoff JB, Frohlich VC, Oleynikov Y, Huttelmaier S, Zavadil J, Cermak L, Bottinger EP, Singer RH, White JG, Segall JE, Condeelis JS. Single cell behavior in metastatic primary mammary tumors correlated with gene expression patterns revealed by molecular profiling. Cancer Res. 2002;62:6278–88.PubMedGoogle Scholar
  21. 21.
    Annunziata CM, Kleinberg L, Davidson B, Berner A, Gius D, Tchabo N, Steinberg SM, Kohn EC. BAG-4/SODD and associated antiapoptotic proteins are linked to aggressiveness of epithelial ovarian cancer. Clin Cancer Res. 2007;13:6585.CrossRefPubMedGoogle Scholar
  22. 22.
    Lemieux P, Oesterreich S, Lawrence J, Steeg P, Hilsenbeck S, Harvey J, Fuqua S. The small heat shock protein hsp27 increases invasiveness but decreases motility of breast cancer cells. Invasion Metastasis. 1997;17:113.PubMedGoogle Scholar
  23. 23.
    Oesterreich S, Weng CN, Qiu M, Hilsenbeck SG, Osborne CK, Fuqua SAW. The small heat shock protein hsp27 is correlated with growth and drug resistance in human breast cancer cell lines. Cancer Res. 1993;53:4443.PubMedGoogle Scholar
  24. 24.
    Zhao M, Shen F, Yin YX, Yang YY, Xiang DJ, Chen Q. Increased expression of heat shock protein 27 correlates with peritoneal metastasis in epithelial ovarian cancer. Reprod Sci. 2011.Google Scholar
  25. 25.
    Sarmiento R, D'Andrea MR, Cacciamani F, Salerno F, Gasparini G. Antiangiogenic therapies in breast cancer. Curr Opin Investig Drugs. 2009;10:1334–45.PubMedGoogle Scholar
  26. 26.
    Kondo S, Asano M, Matsuo K, Ohmori I, Suzuki H. Vascular endothelial growth factor/vascular permeability factor is detectable in the sera of tumor-bearing mice and cancer patients. Biochim Biophys Acta. 1994;1221:211–4.CrossRefPubMedGoogle Scholar
  27. 27.
    Toi M, Hoshina S, Takayanagi T, Tominaga T. Association of vascular endothelial growth factor expression with tumor angiogenesis and with early relapse in primary breast cancer. Jpn J Cancer Res. 1994;85:1045–9.CrossRefPubMedGoogle Scholar
  28. 28.
    Gasparini G. Prognostic value of vascular endothelial growth factor in breast cancer. Oncologist. 2000;5 Suppl 1:37–44.CrossRefPubMedGoogle Scholar
  29. 29.
    Holmgren L, O'Reilly MS, Folkman J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med. 1995;1:149–53.CrossRefPubMedGoogle Scholar
  30. 30.
    O'Reilly MS, Holmgren L, Chen C, Folkman J. Angiostatin induces and sustains dormancy of human primary tumors in mice. Nat Med. 1996;2:689–92.CrossRefPubMedGoogle Scholar
  31. 31.
    Amir E, Seruga B, Serrano R, Ocana A. Targeting DNA repair in breast cancer: a clinical and translational update. Cancer Treat Rev. 2010;36:557–65.CrossRefPubMedGoogle Scholar
  32. 32.
    Agarwal R, Jurisica I, Mills GB, Cheng KW. The emerging role of the RAB25 small GTPase in cancer. Traffic. 2009;10:1561–8.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Gagliardi A, Collins DC. Inhibition of angiogenesis by antiestrogens. Cancer Res. 1993;53:533–5.PubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2012

Authors and Affiliations

  • Y. X. Yin
    • 1
  • F. Shen
    • 2
  • H. Pei
    • 3
  • Y. Ding
    • 1
  • Hua Zhao
    • 1
  • Min Zhao
    • 1
  • Q. Chen
    • 1
    • 4
  1. 1.Wuxi Maternity and Children Health HospitalNanjing Medical UniversityWuxiChina
  2. 2.The Hospital of Obstetrics and GynaecologyFudan UniversityShanghaiChina
  3. 3.Wuxi Fifth People’s HospitalWuxiChina
  4. 4.Department of Obstetrics and GynaecologyThe University of AucklandAucklandNew Zealand

Personalised recommendations