Skip to main content

Advertisement

SpringerLink
Log in

Clinical significance of pAKT and CD44v6 overexpression with breast cancer

  • Original Paper
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

CD44v6 contributes to apoptosis resistance and metastasis via upregulated activity of the PI3K/AKT pathway. The purpose of this study was to investigate the expression patterns and predictive value of phosphorylated AKT (pAKT) and CD44v6 in breast cancer tissues.

Methods

Expression of pAkt and CD44v6 protein was detected using immunohistochemistry in breast cancer tissues and lymph node tissues in 98 patients. The correlation between the expression of pAkt, CD44v6 and other disease-related characteristics was investigated. The prognostic value of pAKT and CD44v6 overexpression for overall survival (OS) and disease free survival (DFS) was determined.

Results

37 cases (37.8%) were observed as positive for pAkt expression, and 38 cases (38.8%) for CD44V6 overexpression. Staining was positive for pAKT in 20 of 38 (52.6%) CD44v6(+) and 17 of 60 (28.3%) CD44v6(−) (P = 0.016). A progressively increased trend of CD44v6 overexpression was observed from node(−) primary breast cancer tissues to node(+) primary cancer tissues to node(+) lymph tissues (P = 0.000). In univariate analysis lymph node status, pAKT and CD44V6 were significantly associated with a decreased OS and DFS. Multivariate analysis revealed that CD44v6 status was associated with a reduced OS (P = 0.003), and pAKT and CD44v6 with a shorter DFS (P = 0.012 and 0.016, respectively).

Conclusions

Our data suggested that there had an intensive relationship between pAKT and CD44v6 expression in breast cancer tissues. The overexpression of CD44v6 was an independent prognostic marker for predicting OS and DFS of breast cancer patients.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Al-Hajj M, Wicha MS, Benito-Hernandez A et al (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100(7):3983–3988

    Article  PubMed  CAS  Google Scholar 

  • Andre F, Nahta R, Conforti R et al (2008) Expression patterns and predictive value of phosphorylated AKT in early-stage breast cancer. Ann Oncol 19(2):315–320

    Article  PubMed  CAS  Google Scholar 

  • Ayroldi E, Cannarile L, Migliorati G et al (1995) CD44 (Pgp-1) inhibits CD3 and dexamethasone-induced apoptosis. Blood 86(7):2672–2678

    PubMed  CAS  Google Scholar 

  • Bates RC, Elith CA, Thorne RF et al (1998) Engagement of variant CD44 confers resistance to anti-integrin antibody-mediated apoptosis in a colon carcinoma cell line. Cell Adhes Commun 6(1):21–38

    Article  PubMed  CAS  Google Scholar 

  • Berner HS, Suo Z, Risberg B et al (2003) Clinicopathological associations of CD44 mRNA and protein expression in primary breast carcinomas. Histopathology 42(6):546–554

    Article  PubMed  CAS  Google Scholar 

  • Bourguignon LY (2008) Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression. Semin Cancer Biol 18(4):251–259

    Article  PubMed  CAS  Google Scholar 

  • Bourguignon LY, Singleton PA, Zhu H et al (2003) Hyaluronan-mediated CD44 interaction with RhoGEF and Rho kinase promotes Grb2-associated binder-1 phosphorylation and phosphatidylinositol 3-kinase signaling leading to cytokine (macrophage-colony stimulating factor) production and breast tumor progression. J Biol Chem 278(32):29420–29434

    Article  PubMed  CAS  Google Scholar 

  • Chalhoub N, Baker SJ (2009) PTEN and the PI3-Kinase pathway in Cancer. Annu Rev Pathol 4:127–150

    Article  PubMed  CAS  Google Scholar 

  • Franke TF, Kaplan DR, Cantley LC (1997) PI3K: downstream AKTion blocks apoptosis. Cell 88(4):435–437

    Article  PubMed  CAS  Google Scholar 

  • Friedrichs K, Franke F, Lisboa BW et al (1995) CD44 isoforms correlate with cellular differentiation but not with prognosis in human breast cancer. Cancer Res 55(22):5424–5433

    PubMed  CAS  Google Scholar 

  • Ghatak S, Misra S, Toole BP (2002) Hyaluronan oligosaccharides inhibit anchorage-independent growth of tumor cells by suppressing the phosphoinositide 3-kinase/Akt cell survival pathway. J Biol Chem 277(41):38013–38020

    Article  PubMed  CAS  Google Scholar 

  • Gunthert U, Hofmann M, Rudy W et al (1991) A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells. Cell 65(1):13–24

    Article  PubMed  CAS  Google Scholar 

  • Gunthert AR, Strater J, von Reyher U et al (1996) Early detachment of colon carcinoma cells during CD95(APO-1/Fas)-mediated apoptosis. I. De-adhesion from hyaluronate by shedding of CD44. J Cell Biol 134(4):1089–1096

    Article  PubMed  CAS  Google Scholar 

  • Herrera-Gayol A, Jothy S (1999) Adhesion proteins in the biology of breast cancer: contribution of CD44. Exp Mol Pathol 66(2):149–156

    Article  PubMed  CAS  Google Scholar 

  • Herrlich P, Zoller M, Pals ST et al (1993) CD44 splice variants: metastases meet lymphocytes. Immunol Today 14(8):395–399

    Article  PubMed  CAS  Google Scholar 

  • Hudson DL, Sleeman J, Watt FM (1995) CD44 is the major peanut lectin-binding glycoprotein of human epidermal keratinocytes and plays a role in intercellular adhesion. J Cell Sci 108(Pt 5):1959–1970

    PubMed  CAS  Google Scholar 

  • Jansen RH, Joosten-Achjanie SR, Arends JW et al (1998) CD44v6 is not a prognostic factor in primary breast cancer. Ann Oncol 9(1):109–111

    Article  PubMed  CAS  Google Scholar 

  • Janssen EA, Soiland H, Skaland I et al (2007) Comparing the prognostic value of PTEN and Akt expression with the Mitotic Activity Index in adjuvant chemotherapy-treated node-negative breast cancer patients aged <55 years. Cell Oncol 29(1):25–35

    PubMed  CAS  Google Scholar 

  • Jones PF, Jakubowicz T, Hemmings BA (1991) Molecular cloning of a second form of rac protein kinase. Cell Regul 2(12):1001–1009

    PubMed  CAS  Google Scholar 

  • Kamikura DM, Khoury H, Maroun C et al (2000) Enhanced transformation by a plasma membrane-associated met oncoprotein: activation of a phosphoinositide 3’-kinase-dependent autocrine loop involving hyaluronic acid and CD44. Mol Cell Biol 20(10):3482–3496

    Article  PubMed  CAS  Google Scholar 

  • Katso R, Okkenhaug K, Ahmadi K et al (2001) Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol 17:615–675

    Article  PubMed  CAS  Google Scholar 

  • Kaufmann M, Heider KH, Sinn HP et al (1995) CD44 variant exon epitopes in primary breast cancer and length of survival. Lancet 345(8950):615–619

    Article  PubMed  CAS  Google Scholar 

  • Kim Y, Lee YS, Choe J et al (2008) CD44-epidermal growth factor receptor interaction mediates hyaluronic acid-promoted cell motility by activating protein kinase C signaling involving Akt, Rac1, Phox, reactive oxygen species, focal adhesion kinase, and MMP-2. J Biol Chem 283(33):22513–22528

    Article  PubMed  CAS  Google Scholar 

  • Klingbeil P, Marhaba R, Jung T et al (2009) CD44 variant isoforms promote metastasis formation by a tumor cell-matrix cross-talk that supports adhesion and apoptosis resistance. Mol Cancer Res 7(2):168–179

    Article  PubMed  CAS  Google Scholar 

  • Knuefermann C, Lu Y, Liu B et al (2003) HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells. Oncogene 22(21):3205–3212

    Article  PubMed  CAS  Google Scholar 

  • Lee JL, Wang MJ, Sudhir PR et al (2007) Osteopontin promotes integrin activation through outside-in and inside-out mechanisms: OPN-CD44V interaction enhances survival in gastrointestinal cancer cells. Cancer Res 67(5):2089–2097

    Article  PubMed  CAS  Google Scholar 

  • Lester BR, McCarthy JB (1992) Tumor cell adhesion to the extracellular matrix and signal transduction mechanisms implicated in tumor cell motility, invasion and metastasis. Cancer Metastasis Rev 11(1):31–44

    Article  PubMed  CAS  Google Scholar 

  • Ma W, Deng Y, Zhou L (2005) The prognostic value of adhesion molecule CD44v6 in women with primary breast carcinoma: a clinicopathologic study. Clin Oncol (R Coll Radiol) 17(4):258–263

    CAS  Google Scholar 

  • Marhaba R, Freyschmidt-Paul P, Zoller M (2006) In vivo CD44-CD49d complex formation in autoimmune disease has consequences on T cell activation and apoptosis resistance. Eur J Immunol 36(11):3017–3032

    Article  PubMed  CAS  Google Scholar 

  • Modi S, DiGiovanna MP, Lu Z et al (2005) Phosphorylated/activated HER2 as a marker of clinical resistance to single agent taxane chemotherapy for metastatic breast cancer. Cancer Invest 23(6):483–487

    Article  PubMed  CAS  Google Scholar 

  • Sarbassov DD, Guertin DA, Ali SM et al (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307(5712):1098–1101

    Article  PubMed  CAS  Google Scholar 

  • Schmitz KJ, Otterbach F, Callies R et al (2004) Prognostic relevance of activated Akt kinase in node-negative breast cancer: a clinicopathological study of 99 cases. Mod Pathol 17(1):15–21

    Article  PubMed  CAS  Google Scholar 

  • Stal O, Perez-Tenorio G, Akerberg L et al (2003) Akt kinases in breast cancer and the results of adjuvant therapy. Breast Cancer Res 5(2):R37–R44

    Article  PubMed  CAS  Google Scholar 

  • Subramaniam V, Vincent IR, Gardner H et al (2007) CD44 regulates cell migration in human colon cancer cells via Lyn kinase and AKT phosphorylation. Exp Mol Pathol 83(2):207–215

    Article  PubMed  CAS  Google Scholar 

  • Sun M, Wang G, Paciga JE et al (2001) AKT1/PKBalpha kinase is frequently elevated in human cancers and its constitutive activation is required for oncogenic transformation in NIH3T3 cells. Am J Pathol 159(2):431–437

    PubMed  CAS  Google Scholar 

  • Tokunaga E, Kataoka A, Kimura Y et al (2006a) The association between Akt activation and resistance to hormone therapy in metastatic breast cancer. Eur J Cancer 42(5):629–635

    Article  PubMed  CAS  Google Scholar 

  • Tokunaga E, Kimura Y, Oki E et al (2006b) Akt is frequently activated in HER2/neu-positive breast cancers and associated with poor prognosis among hormone-treated patients. Int J Cancer 118(2):284–289

    Article  PubMed  CAS  Google Scholar 

  • Tulasne D, Foveau B (2008) The shadow of death on the MET tyrosine kinase receptor. Cell Death Differ 15(3):427–434

    Article  PubMed  CAS  Google Scholar 

  • Wu Y, Mohamed H, Chillar R et al (2008) Clinical significance of Akt and HER2/neu overexpression in African-American and Latina women with breast cancer. Breast Cancer Res 10(1):R3

    Article  PubMed  CAS  Google Scholar 

  • Zhou X, Tan M, Stone Hawthorne V et al (2004) Activation of the Akt/mammalian target of rapamycin/4E-BP1 pathway by ErbB2 overexpression predicts tumor progression in breast cancers. Clin Cancer Res 10(20):6779–6788

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of interest statement

We declare that we have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of General Surgery, First People’s Hospital of Shanghai Jiaotong University, Hongkou District, Room 314, Building 9, No. 85 Wujing Road, Shanghai, China

    Pei Yu, Ling Zhou, Weifeng Ke & Ke Li

Authors
  1. Pei Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ling Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Weifeng Ke
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ke Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ke Li.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yu, P., Zhou, L., Ke, W. et al. Clinical significance of pAKT and CD44v6 overexpression with breast cancer. J Cancer Res Clin Oncol 136, 1283–1292 (2010). https://doi.org/10.1007/s00432-010-0779-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-010-0779-x

Keywords

Search

Navigation