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Cellular Oncology

, Volume 36, Issue 6, pp 485–491 | Cite as

Increase in ezrin expression from benign to malignant breast tumours

  • Daphne Gschwantler-KaulichEmail author
  • Camilla Natter
  • Stefan Steurer
  • Ingrid Walter
  • Almut Thomas
  • Mohamed Salama
  • Christian F. Singer
Original Paper

Abstract

Purpose

Ezrin is known to be involved in intercellular interactions, and a shift from membrane-bound to cytoplasmatic protein expression has been associated with malignant potential. This association has primarily been demonstrated in cell lines and, as yet, little is known about the distribution of ezrin in primary benign and malignant breast tissues. We have, therefore, set out to investigate ezrin protein expression in a series of primary breast lesions.

Methods

Immunohistochemistry was used to detect ezrin expression in 465 samples of normal breast tissues, benign breast tumours, pre-invasive breast lesions, breast cancer tissues and metastatic lymph nodes, and the protein expression patterns observed were correlated with clinicopathological parameters.

Results

Ezrin was detected in the cytoplasm of both benign and malignant breast tissues, but its expression was significantly higher in the malignant tissues (13 % vs 60 %, p < 0.0001; χ 2 test). We also detected a statistically significant higher ezrin expression in pre-invasive lesions compared to benign lesions (15 % vs 44 %, p = 0.04; χ 2 test). We did not find such a difference in ezrin expression between pre-invasive and invasive cancer samples, nor between invasive cancer samples and lymph node metastases. Within the group of invasive cancer samples, we found a significant correlation between ezrin expression and CK14 (rs:0.38, p < 0.007) and Her2 (rs:0.25, p < 0.002) expression. No such correlation was observed between ezrin expression and nodal status, grading, patient’s age, hormone receptor status, and Ki67 or p53 expression.

Conclusion

Taken together, we found that cytoplasmatic ezrin expression increases from benign to malignant breast tumour development. We hypothesize that the tissue architectural alterations that are associated with aberrant ezrin expression may point at pathophysiological mechanisms that may be instrumental for the design of novel therapies.

Keywords

Ezrin Breast cancer Tumour invasion Metastasis 

Notes

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    K.A. Swanson, D.D. Crane, H.D. Caldwell, Chlamydia trachomatis species-specific induction of ezrin tyrosine phosphorylation functions in pathogen entry. Infect. Immun. 75, 5669–5677 (2007)PubMedCrossRefGoogle Scholar
  2. 2.
    A. Fadiel, H.H. Lee, N. Demir, S. Richman, A. Iwasaki, K. Connell, F. Naftolin, Ezrin is a key element in the human vagina. Maturitas 60, 31–41 (2008)PubMedCrossRefGoogle Scholar
  3. 3.
    A. Bretscher, Regulation of cortical structure by the ezrin-radixin-moesin protein family. Curr. Opin. Cell Biol. 11, 109–116 (1999)PubMedCrossRefGoogle Scholar
  4. 4.
    S. Tsukita, S. Yonemura, S. Tsukita, ERM (ezrin/radixin/moesin) family: from cytoskeleton to signal transduction. Curr. Opin. Cell Biol. 9, 70–75 (1997)PubMedCrossRefGoogle Scholar
  5. 5.
    S. Fais, A role for ezrin in a neglected metastatic tumor function. Trends Mol. Med. 10, 249–250 (2004)PubMedCrossRefGoogle Scholar
  6. 6.
    S. Tsukita, K. Oishi, N. Sato, J. Sagara, A. Kawai, S. Tsukita, ERM family members as molecular linkers between the cell surface glycoprotein CD44 and actin-based cytoskeletons. J. Cell Biol. 126, 391–401 (1994)PubMedCrossRefGoogle Scholar
  7. 7.
    S. Yonemura, M. Hirao, Y. Doi, N. Takahashi, T. Kondo, S. Tsukita, S. Tsukita, Ezrin/radixin/moesin (ERM) proteins bind to a positively charged amino acid cluster in the juxta-membrane cytoplasmic domain of CD44, CD43, and ICAM-2. J. Cell Biol. 140, 885–895 (1998)PubMedCrossRefGoogle Scholar
  8. 8.
    M. Curto, A.I. McClatchey, Ezrin…a metastatic detERMinant? Cancer Cell 5, 113–114 (2004)PubMedCrossRefGoogle Scholar
  9. 9.
    D.T. Dransfield, A.J. Bradford, J. Smith, M. Martin, C. Roy, P.H. Mangeat, J.R. Goldenring, Ezrin is a cyclic AMP-dependent protein kinase anchoring protein. EMBO J. 16, 35–43 (1997)PubMedCrossRefGoogle Scholar
  10. 10.
    K.W. Hunter, Ezrin, a key component in tumor metastasis. Trends Mol. Med. 10, 201–204 (2004)PubMedCrossRefGoogle Scholar
  11. 11.
    X. Yao, L. Cheng, J.G. Forte, Biochemical characterization of ezrin-actin interaction. J. Biol. Chem. 271, 7224–7229 (1996)PubMedCrossRefGoogle Scholar
  12. 12.
    P. Pujuguet, L. Del Maestro, A. Gautreau, D. Louvard, M. Arpin, Ezrin regulates E-cadherin-dependent adherens junction assembly through Rac1 activation. Mol. Biol. Cell 14, 2181–2191 (2003)PubMedCrossRefGoogle Scholar
  13. 13.
    M. Berryman, Z. Franck, A. Bretscher, Ezrin is concentrated in the apical microvilli of a wide variety of eptihelial cells whereas moesin is found primarily in endothelial cells. J. Cell Sci. 105, 1025–1043 (1993)PubMedGoogle Scholar
  14. 14.
    A. Gautreau, P. Poullet, D. Louvard, M. Arpin, Ezrin, a plasma memrane- microfilament linker, signals cell survival through the phosphatidylinositol 3- kinase/Akt pahtway. Proc. Natl. Acad. Sci. U. S. A. 96, 7300–7305 (1999)PubMedCrossRefGoogle Scholar
  15. 15.
    A.I. McClatchey, Merlin and ERM proteins: unappreciated roles in cancer development? Nat. Rev. Cancer 3, 877–883 (2003)PubMedCrossRefGoogle Scholar
  16. 16.
    B. Bruce, G. Khanna, L. Ren, G. Landberg, K. Jirström, C. Powell, A. Borczuk, E.T. Keller, K.J. Wojno, P. Meltzer, K. Baird, A. McClatchey, A. Bretscher, S.M. Hewitt, C. Khanna, Expression of the cytoskeleton linker protein ezrin in human cancers. Clin. Exp. Metastasis 24, 69–78 (2007)PubMedCrossRefGoogle Scholar
  17. 17.
    T.A. Martin, G. Harriso, R.E. Mansel, W.G. Jiang, The role of the CD44/ezrin complex in cancer metastasis. Crit. Rev. Oncol. Hematol. 46, 165–186 (2003)PubMedCrossRefGoogle Scholar
  18. 18.
    A. Gautreau, D. Louvard, M. Arpin, ERM proteins and NF2 tumor suppressor: the Yin and Yang of cortical actin organization and cell growth signaling. Curr. Opin. Cell Biol. 14, 104–109 (2002)PubMedCrossRefGoogle Scholar
  19. 19.
    N. Koon, R. Schneider-Stock, M. Sarlomo-Rikala, J. Lasota, M. Smolkin, G. Petroni, A. Zaika, C. Boltze, F. Meyer, L. Andersson, S. Knuutila, M. Miettinen, W. El-Rifai, Molecular targets for tumour progression in gastrointestinal stromal tumours. Gut 53, 235–240 (2004)PubMedCrossRefGoogle Scholar
  20. 20.
    S.C. Kaul, Y. Mitsui, Y. Komatsu, R.R. Reddel, R. Wadhwa, A highly expressed 81kDa protein in immortalized mouse fibroblast: its proliferative function and identity with ezrin. Oncogene 13, 1231–1237 (1996)PubMedGoogle Scholar
  21. 21.
    Z.Y. Shen, L.Y. Xu, M.H. Chen, E.M. Li, J.T. Li, X.Y. Wu, Y. Zeng, Upregulated expression of Ezrin and invasive phenotype in malignantly transformed esophageal epithelial cells. World J. Gastroenterol. 9, 1182–1186 (2003)PubMedGoogle Scholar
  22. 22.
    K. Ohtani, H. Sakamoto, T. Rutherford, Z. Chen, K. Satoh, F. Naftolin, Ezrin, a membrane-cytoskeletal linking protein, is involved in the process of invasion of endometrial cancer cells. Cancer Lett. 147, 31–38 (1999)PubMedCrossRefGoogle Scholar
  23. 23.
    C. Khanna, J. Khan, P. Nguyen, J. Prehn, J. Caylor, C. Yeung, J. Trepel, P. Meltzer, L. Helman, Metastasis-associated differences in gene expression in a murine model of osteosarcoma. Cancer Res. 61, 3750–3759 (2001)PubMedGoogle Scholar
  24. 24.
    C. Khanna, X. Wan, S. Bose, R. Cassaday, O. Olomu, A. Mendoza, C. Yeung, R. Gorlic, S.M. Hewitt, L.J. Helman, The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis. Nat. Med. 10, 182–186 (2004)PubMedCrossRefGoogle Scholar
  25. 25.
    S. Ferrari, L. Zanella, M. Alberghini, E. Palmerini, E. Staals, P. Bacchini, Prognostic significance of immunohistochemical expression of ezrin in non-metastatic high-grade osteosarcoma. Pediatr. Blood Cancer 50, 752–756 (2008)PubMedCrossRefGoogle Scholar
  26. 26.
    Y. Yu, J. Khan, C. Khanna, L. Helman, P.S. Meltzer, G. Merlino, Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators. Nat. Med. 10, 175–181 (2004)PubMedCrossRefGoogle Scholar
  27. 27.
    N. Akisawa, I. Nishimori, T. Iwamura, S. Onishi, M.A. Hollingsworth, High levels of ezrin expressed by human pancreatic adenocarcinoma cell lines with high metastatic potential. Biochem. Biophys. Res. Commun. 258, 395–400 (1999)PubMedCrossRefGoogle Scholar
  28. 28.
    H.J. Wang, J.S. Zhu, Q. Zhang, Q. Sun, H. Guo, High level of ezrin expression in colorectal cancer tissues is closely related to tumor malignancy. World J. Gastroenterol. 15, 2016–2019 (2009)PubMedCrossRefGoogle Scholar
  29. 29.
    J. Musiał, S. Sporny, A. Nowicki, Prognostic significance of E-cadherin and ezrin immunohistochemical expression in prostate cancer. Pol. J. Pathol. 58, 235–243 (2007)PubMedGoogle Scholar
  30. 30.
    S.T. Pang, X. Fang, A. Valdman, G. Norstedt, A. Pousette, L. Egevad, P. Ekman, Expression of ezrin in prostatic intraepithelial neoplasia. Urology 63, 609–612 (2004)PubMedCrossRefGoogle Scholar
  31. 31.
    Z. Chen, A. Fadiel, Y. Feng, K. Ohtani, T. Rutherford, F. Naftolin, Ovarian epithelial carcinoma tyrosine phosphorylation, cell proliferation, and ezrin translocation are stimulated by interleukin 1alpha and epidermal growth factor. Cancer 92, 3068–3075 (2001)PubMedCrossRefGoogle Scholar
  32. 32.
    K. Ohtani, H. Sakamoto, T. Rutherford, Z. Chen, A. Kikuchi, T. Yamamoto, K. Satoh, F. Naftolin, Ezrin, a membrane-cytoskeletal linking protein, is highly expressed in atypical endometrial hyperplasia and uterine endometrioid adenocarcinoma. Cancer Lett. 179, 79–86 (2002)PubMedCrossRefGoogle Scholar
  33. 33.
    B.E. Elliott, J.A. Meens, S.K. SenGupta, D. Louvard, M. Arpin, The membrane cytoskeletal crosslinker ezrin is required for metastasis of breast carcinoma cells. Breast Cancer Res. 7, R365–R373 (2005)PubMedCrossRefGoogle Scholar
  34. 34.
    Q. Li, M. Wu, H. Wang, G. Xu, T. Zhu, Y. Zhang, P. Liu, A. Song, C. Gang, Z. Han, J. Zhou, L. Meng, Y. Lu, S. Wang, D. Ma, Ezrin silencing by small hairpin RNA reverses metastatic behaviors of human breast cancer cells. Cancer Lett. 261, 55–63 (2008)PubMedCrossRefGoogle Scholar
  35. 35.
    E.D. Coene, C. Gadelha, N. White, A. Malhas, B. Thomas, M. Shaw, D.J. Vaux, A novel role for BRCA1 in regulating breast cancer cell spreading and motility. J. Cell Biol. 192, 497–512 (2011)PubMedCrossRefGoogle Scholar
  36. 36.
    D. Sarrio, S.M. Rodriguez-Pinilla, A. Dotor, F. Calero, D. Hardisson, J. Palacios, Abnormal ezrin localization is associated with clinicopathological features in invasive breast carcinomas. Breast Cancer Res. Treat. 98, 71–79 (2006)PubMedCrossRefGoogle Scholar
  37. 37.
    A. Halon, P. Donizy, P. Surowiak, R. Matkowski, ERM/Rho protein expression in ductal breast cancer: a 15 year follow-up. Cell. Oncol. (2013, Feb 19).Google Scholar
  38. 38.
    A.A. Arslan, D. Silvera, R. Arju, S. Giashuddin, I. Belitskaya-Levy, S.C. Formenti, R.J. Schneider, Atypical ezrin localization as a marker of locally advanced breast cancer. Breast Cancer Res. Treat. 134, 981–988 (2012)PubMedCrossRefGoogle Scholar
  39. 39.
    J. Moilanen, H. Lassus, A. Leminen, A. Vaheri, R. Butzow, O. Carpen, Ezrin immunoreactivity in relation to survival in serous ovarian carcinoma patients. Gynecol. Oncol. 90, 273–281 (2003)PubMedCrossRefGoogle Scholar
  40. 40.
    K.D. Geiger, P. Stoldt, W. Schlote, A. Derouiche, Ezrin immunoreactivity is associated with increasing malignancy of astrocytic tumors but is absent in oligodendrogliomas. Am. J. Pathol. 157, 1785–1793 (2000)PubMedCrossRefGoogle Scholar
  41. 41.
    S. Ilmonen, A. Vaheri, S. Asko-Seljavaara, O. Carpen, Ezrin in primary cutaneous melanoma. Mod. Pathol. 2, 1–8 (2004)Google Scholar
  42. 42.
    S. Zheng, J. Huang, K. Zhou, C. Zhang, Q. Xiang, Z. Tan, T. Wang, X. Fu, 17β-estradiol enhances breast cancer cell motility and invasion via extra-nuclear activation of actin-binding protein ezrin. PLoS ONE 6, e22439 (2011)PubMedCrossRefGoogle Scholar
  43. 43.
    L. Ma, X.H. Zhang, L.X. Xing, Y.H. Li, X.L. Wang, Y.J. Wang, Relationship of ezrin protein expression to the carcinogenesis and prognosis of infiltrating breast ductal carcinoma. Zhonghua Zhong Liu Za Zhi 30, 279–283 (2008)PubMedGoogle Scholar
  44. 44.
    F. Rastelli, S. Biancanelli, A. Falzetta, A. Martignetti, C. Casi, R. Bascioni, L. Giustini, S. Crispino, Triple- negative breast cancer: current state of the art. Tumori 96, 875–888 (2010)PubMedGoogle Scholar
  45. 45.
    Q. Li, M.F. Wu, A.P. Song, J.C. Wei, G. Xu, Y.P. Lu, D. Ma, Expression of ezrin and e-cadherin in invasive ductal breast cancer and their correlations to lymphatic metastasis. Ai Zheng 25, 363–366 (2006)PubMedGoogle Scholar
  46. 46.
    L. Ma, Y.P. Liu, X.H. Zhang, C.Z. Geng, Z.H. Li, Relationship of RhoA signaling activity with ezrin expression and ist significance in the prognosis for breast cancer patients. Chin. Med. J. 126, 242–247 (2013)PubMedGoogle Scholar

Copyright information

© International Society for Cellular Oncology 2013

Authors and Affiliations

  • Daphne Gschwantler-Kaulich
    • 1
    Email author
  • Camilla Natter
    • 1
  • Stefan Steurer
    • 2
  • Ingrid Walter
    • 3
  • Almut Thomas
    • 4
  • Mohamed Salama
    • 5
  • Christian F. Singer
    • 1
  1. 1.Department of OB/GYN, Division of General Gynecology and Gynecologial OncologyMedical University of ViennaViennaAustria
  2. 2.Department of PathologyUniversity Hospital Hamburg EppendorfHamburgGermany
  3. 3.Institute of Anatomy, Histology, and EmbryologyUniversity of Veterinary MedicineViennaAustria
  4. 4.University of KlagenfurtKlagenfurtAustria
  5. 5.Department of Thoracic SurgeryOtto Wagner SpitalViennaAustria

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