Advertisement

Tumor Biology

, Volume 35, Issue 7, pp 6425–6434 | Cite as

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

  • Emil Štajduhar
  • Mirela Sedić
  • Tanja Leniček
  • Petra Radulović
  • Aleksandar Kerenji
  • Božo Krušlin
  • Krešimir Pavelić
  • Sandra Kraljević PavelićEmail author
Research Article

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.

Keywords

Breast cancer Metastasis Growth hormone Growth hormone receptor Plakoglobin NEDD9 

Notes

Acknowledgments

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

Supplementary material

13277_2014_1827_MOESM1_ESM.docx (26 kb)
ESM 1 (DOCX 25 kb)
13277_2014_1827_MOESM2_ESM.docx (26 kb)
ESM 2 (DOCX 25 kb)
13277_2014_1827_MOESM3_ESM.docx (26 kb)
ESM 3 (DOCX 25 kb)
13277_2014_1827_MOESM4_ESM.docx (196 kb)
ESM 4 (DOCX 196 kb)
13277_2014_1827_MOESM5_ESM.docx (45 kb)
ESM 5 (DOCX 45 kb)

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.CrossRefPubMedGoogle Scholar
  2. 2.
    Nguyen DX, Massague J. Genetic determinants of cancer metastasis. Nat Rev Genet. 2007;8:341–52.CrossRefPubMedGoogle Scholar
  3. 3.
    Weigelt B, Peterse JL, van 't Veer LJ. Breast cancer metastasis: markers and models. Nat Rev Cancer. 2005;5:591–602.CrossRefPubMedGoogle Scholar
  4. 4.
    Blanco MA, Kang Y. Signaling pathways in breast cancer metastasis—novel insights from functional genomics. Breast Cancer Res. 2011;13:206.PubMedCentralCrossRefPubMedGoogle 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.PubMedCentralCrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.PubMedCentralCrossRefPubMedGoogle 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.PubMedCentralCrossRefPubMedGoogle 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.PubMedCentralCrossRefPubMedGoogle 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.PubMedCentralCrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.PubMedCentralCrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.PubMedGoogle 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.PubMedGoogle 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.CrossRefPubMedGoogle 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.PubMedGoogle 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.CrossRefPubMedGoogle Scholar
  20. 20.
    Aktary Z, Pasdar M. Plakoglobin: role in tumorigenesis and metastasis. Int J Cell Biol. 2012;2012:189521.PubMedCentralCrossRefPubMedGoogle 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.PubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.PubMedCentralCrossRefPubMedGoogle 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.PubMedCentralCrossRefPubMedGoogle 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.PubMedCentralCrossRefPubMedGoogle 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.PubMedGoogle 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.PubMedCentralCrossRefPubMedGoogle 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.PubMedCentralCrossRefPubMedGoogle 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.PubMedGoogle 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.PubMedCentralCrossRefPubMedGoogle 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.PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Emil Štajduhar
    • 1
  • Mirela Sedić
    • 2
  • Tanja Leniček
    • 1
  • Petra Radulović
    • 1
  • Aleksandar Kerenji
    • 2
  • Božo Krušlin
    • 1
    • 3
  • Krešimir Pavelić
    • 2
  • Sandra Kraljević Pavelić
    • 2
    Email author
  1. 1.Sestre Milosrdnice Clinical Hospital CenterZagrebCroatia
  2. 2.Department of BiotechnologyUniversity of RijekaRijekaCroatia
  3. 3.Department of Pathology, School of MedicineUniversity of ZagrebZagrebCroatia

Personalised recommendations