Expression of growth hormone receptor, plakoglobin and NEDD9 protein in association with tumour progression and metastasis in human breast cancer

Abstract

Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer-related deaths among female population worldwide. Metastases are the common cause of morbidity and mortality in breast cancer and can remain latent for several years after surgical removal of the primary tumour. Thus, the identification and functional characterisation of molecular factors that promote oncogenic signalling in mammary tumour development and progression could provide new entry points for designing targeted therapeutic strategies for metastatic breast cancer. In the present study, we investigated the expression of proteins involved in cell signalling (growth hormone receptor (GHR) and NEDD9) and cell-cell adhesion (plakoglobin) in epithelial and stromal compartments of primary ductal invasive breast carcinomas and their axillary lymph node metastases versus non-metastatic tumours. Obtained data revealed remarkable increase in the expression levels of GHR and NEDD9 proteins in both epithelial and stromal components of axillary lymph node metastases in comparison with those of non-metastatic tumours, suggesting that the expression of these two proteins may provide biomarkers for tumour aggressiveness.

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References

  1. 1.

    Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature. 2000;406:747–52.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Nguyen DX, Massague J. Genetic determinants of cancer metastasis. Nat Rev Genet. 2007;8:341–52.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Weigelt B, Peterse JL, van 't Veer LJ. Breast cancer metastasis: markers and models. Nat Rev Cancer. 2005;5:591–602.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Blanco MA, Kang Y. Signaling pathways in breast cancer metastasis—novel insights from functional genomics. Breast Cancer Res. 2011;13:206.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  5. 5.

    Holen I, Whitworth J, Nutter F, Evans A, Brown HK, Lefley DV, et al. Loss of plakoglobin promotes decreased cell-cell contact, increased invasion and breast cancer cell dissemination in vivo. Breast Cancer Res. 2012;14:R86.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  6. 6.

    Bukholm IK, Nesland JM, Borresen-Dale AL. Re-expression of E-cadherin, alpha-catenin and beta-catenin, but not of gamma-catenin, in metastatic tissue from breast cancer patients [seecomments]. J Pathol. 2000;190:15–9.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Yin T, Getsios S, Caldelari R, Kowalczyk AP, Muller EJ, Jones JC, et al. Plakoglobin suppresses keratinocyte motility through both cell-cell adhesion-dependent and -independent mechanisms. Proc Natl Acad Sci U S A. 2005;102:5420–5.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  8. 8.

    Todorovic V, Desai BV, Patterson MJ, Amargo EV, Dubash AD, Yin T, et al. Plakoglobin regulates cell motility through Rho- and fibronectin-dependent Src signaling. J Cell Sci. 2010;123:3576–86.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  9. 9.

    Bailey CK, Mittal MK, Misra S, Chaudhuri G. High motility of triple-negative breast cancer cells is due to repression of plakoglobin gene by metastasis modulator protein SLUG. J Biol Chem. 2012;287:19472–86.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  10. 10.

    Gebre-Medhin M, Kindblom LG, Wennbo H, Tornell J, Meis-Kindblom JM. Growth hormone receptor is expressed in human breast cancer. Am J Pathol. 2001;158:1217–22.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  11. 11.

    Chiesa J, Ferrer C, Arnould C, Vouyovitch CM, Diaz JJ, Gonzalez S, et al. Autocrine proliferative effects of hGH are maintained in primary cultures of human mammary carcinoma cells. J Clin Endocrinol Metab. 2011;96(9):E1418–26.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Bradshaw LN, Zhong J, Bradbury P, Mahmassani M, Smith JL, Ammit AJ, et al. Estradiol stabilizes the 105-kDa phospho-form of the adhesion docking protein NEDD9 and suppresses NEDD9-dependent cell spreading in breast cancer cells. Biochim Biophys Acta. 1813;2011:340–5.

    Google Scholar 

  13. 13.

    Singh MK, Izumchenko E, Klein-Szanto AJ, Egleston BL, Wolfson M, Golemis EA. Enhanced genetic instability and dasatinib sensitivity in mammary tumor cells lacking NEDD9. Cancer Res. 2010;70:8907–16.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  14. 14.

    Yap AS. Manley SW Contact inhibition of cell spreading: a mechanism for the maintenance of thyroid cell aggregation in vitro. Exp Cell Res. 1993;208:121–7.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Pavelic K, Bulbul MA, Slocum HK, Pavelic ZP, Rustum YM, Niedbala MJ, et al. Growth of human urological tumors on extracellular matrix as a model for the in vitro cultivation of primary human tumor explants. Cancer Res. 1986;46:3653–62.

    CAS  PubMed  Google Scholar 

  16. 16.

    Kaulsay KK, Mertani HC, Lee K-O, Lobie PE. Autocrine human growth hormone enhancement of human mammary carcinoma cell spreading is Jak2 dependent. Endocrinology. 2000;141:1571–84.

    CAS  PubMed  Google Scholar 

  17. 17.

    Handschuh G, Candidus S, Luber B, Reich U, Schott C, Oswald S, et al. Tumour-associated E-cadherin mutations alter cellular morphology, decrease cellular adhesion and increase cellular motility. Oncogene. 1999;18:4301–12.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Kővári B, Rusz O, Schally AV, Kahán Z, Cserni G. Differential immunostaining of various types of breast carcinomas for growth hormone-releasing hormone receptor—apocrine epithelium and carcinomas emerging as uniformly positive. APMIS. 2014. doi:10.1111/apm.12224.

    PubMed  Google Scholar 

  19. 19.

    Mertani HC, Garcia-Caballero T, Lambert A, Gerard F, Palayer C, Boutin JM, et al. Cellular expression of growth hormone and prolactin receptors in human breast disorders. Int J Cancer. 1998;79:202–11.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Aktary Z, Pasdar M. Plakoglobin: role in tumorigenesis and metastasis. Int J Cell Biol. 2012;2012:189521.

    PubMed Central  Article  PubMed  Google Scholar 

  21. 21.

    Sommers CL, Gelmann EP, Kemler R, Cowin P, Byers SW. Alterations in beta-catenin phosphorylation and plakoglobin expression in human breast cancer cells. Cancer Res. 1994;54:3544–52.

    CAS  PubMed  Google Scholar 

  22. 22.

    Park D, Karesen R, Axcrona U, Noren T, Sauer T. Expression pattern of adhesion molecules (E-cadherin, alpha-, beta-, gamma-catenin and claudin-7), their influence on survival in primary breast carcinoma, and their corresponding axillary lymph node metastasis. APMIS. 2007;115:52–65.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Bukholm IK, Nesland JM, Karesen R, Jacobsen U, Borresen-Dale AL. E-cadherin and alpha-, beta-, and gamma-catenin protein expression in relation to metastasis in human breast carcinoma. J Pathol. 1998;185:262–6.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Mukhina S, Mertani HC, Guo K, Lee KO, Gluckman PD, Lobie PE. Phenotypic conversion of human mammary carcinoma cells by autocrine human growth hormone. Proc Natl Acad Sci U S A. 2004;101:15166–71.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  25. 25.

    Williamson L, Raess NA, Caldelari R, Zakher A, de Bruin A, Posthaus H, et al. Pemphigus vulgaris identifies plakoglobin as key suppressor of c-Myc in the skin. EMBO J. 2006;25:3298–309.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  26. 26.

    Shtutman M, Zhurinsky J, Oren M, Levina E, Ben-Ze'ev A. PML is a target gene of β-catenin and plakoglobin, and coactivates β-catenin-mediated transcription. Cancer Res. 2002;62:947–54.

    Google Scholar 

  27. 27.

    Goyal A, Martin TA, Mansel RE, Jiang WG. Real time PCR analyses of expression of E-cadherin, alpha-, beta- and gamma-catenin in human breast cancer for predicting clinical outcome. World J Surg Oncol. 2008;6:56.

    PubMed Central  Article  PubMed  Google Scholar 

  28. 28.

    Schonborn I, Zschiesche W, Behrens J, Herrenknecht K, Birchmeier W. Expression of E-cadherin/catenin complexes in breast cancer. Int J Oncol. 1997;11:1327–34.

    CAS  PubMed  Google Scholar 

  29. 29.

    Salomon D, Sacco PA, Roy SG, Simcha I, Johnson KR, Wheelock MJ, et al. Regulation of β-catenin levels and localization by overexpression of plakoglobin and inhibition of the ubiquitin-proteasome system. J Cell Biol. 1997;139:1325–35.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  30. 30.

    Klymkowsky MW, Williams BO, Barish GD, Varmus HE, Vourgourakis YE. Membrane-anchored plakoglobins have multiple mechanisms of action in Wnt signaling. Mol Biol Cell. 1999;10:3151–69.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  31. 31.

    Fashena SJ, Einarson MB, O'Neill GM, Patriotis C, Golemis EA. Dissection of HEF1-dependent functions in motility and transcriptional regulation. J Cell Sci. 2002;115:99–111.

    CAS  PubMed  Google Scholar 

  32. 32.

    Izumchenko E, Singh MK, Plotnikova OV, Tikhmyanova N, Little JL, Serebriiskii IG, et al. NEDD9 promotes oncogenic signaling in mammary tumor development. Cancer Res. 2009;69:7198–206.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  33. 33.

    Kong C, Wang C, Wang L, Ma M, Niu C, Sun X, et al. NEDD9 is a positive regulator of epithelial-mesenchymal transition and promotes invasion in aggressive breast cancer. PLoS One. 2011;6:e22666.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

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Acknowledgments

The work was supported by the Ministry of Science Education and Sports projects 335-0982464-239, 335-0000000-3532 and 108-1081870-1884.

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Correspondence to Sandra Kraljević Pavelić.

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Štajduhar, E., Sedić, M., Leniček, T. et al. Expression of growth hormone receptor, plakoglobin and NEDD9 protein in association with tumour progression and metastasis in human breast cancer. Tumor Biol. 35, 6425–6434 (2014). https://doi.org/10.1007/s13277-014-1827-y

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Keywords

  • Breast cancer
  • Metastasis
  • Growth hormone
  • Growth hormone receptor
  • Plakoglobin
  • NEDD9