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Breast Cancer Research and Treatment

, Volume 116, Issue 1, pp 103–111 | Cite as

Expression of coxsackie-adenovirus receptor is related to estrogen sensitivity in breast cancer

  • Doris Auer
  • Daniel Reimer
  • Verena Porto
  • Martina Fleischer
  • Julia Roessler
  • Annemarie Wiedemair
  • Christian Marth
  • Elisabeth Müller-Holzner
  • Günter Daxenbichler
  • Alain G. ZeimetEmail author
Preclinical Study

Abstract

This study analyzes the relationship between coxsackie-adenovirus receptor (CAR) expression (transmembrane and soluble isoforms) and hormone sensitivity in 95 breast cancers. Furthermore, prognostic significance of the expression of the various CAR isoforms was investigated. In addition, inducibility of CAR expression by estradiol and tamoxifen was assessed in various breast cancer cell lines. Expression of transmembrane CAR (hCAR) highly correlated with estrogen receptivity, but was independent of the expression of progesterone receptor (PR). Furthermore, hCAR expression was significantly higher in tumors with low-grade malignancy. However, no relationship between hCAR expression and tumor size, lymph node status, or survival was revealed. In the hormone receptor-positive breast cancer cell line T47-D expression of hCAR and its soluble isoforms was increased by treatment with estradiol and tamoxifen. In contrast, no induction of either CAR isoform was achieved in receptor-negative cell lines. Furthermore, enhancement of hCAR expression was significantly greater when cells were treated with the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) than when treated with estradiol or tamoxifen. Moreover, sensitivity to TSA induction of hCAR was considerably greater in receptor-positive than in receptor-negative cell lines. No additive effect on CAR expression was found when TSA was combined with either estradiol or tamoxifen. In conclusion, the so far undescribed association between estrogen receptivity and the expression of hCAR in breast cancer seems to not only reflect a phenotype of low malignancy, but expression of hCAR may also be directly influenced by ER-specific ligands.

Keywords

Breast cancer Coxsackie-adenovirus receptor Estrogen receptor HDAC inhibitor Hormone sensitivity Tamoxifen 

References

  1. 1.
    Matsumoto K, Shariat SF, Ayala GE, Rauen KA, Lerner SP (2005) Loss of coxsackie and adenovirus receptor expression is associated with features of aggressive bladder cancer. Urology 66:441–446. doi: 10.1016/j.urology.2005.02.033 PubMedCrossRefGoogle Scholar
  2. 2.
    Cohen CJ, Shieh JT, Pickles RJ, Okegawa T, Hsieh JT, Bergelson JM (2001) The coxsackievirus and adenovirus receptor is a transmembrane component of the tight junction. Proc Natl Acad Sci USA 98:15191–15196. doi: 10.1073/pnas.261452898 PubMedCrossRefGoogle Scholar
  3. 3.
    Williams AF, Barclay AN (1988) The immunoglobulin superfamily—domains for cell surface recognition. Annu Rev Immunol 6:381–405PubMedGoogle Scholar
  4. 4.
    Chen JW, Ghosh R, Finberg W, Bergelson JM (2003) Structure and chromosomal localization of the murine coxsackievirus and adenovirus receptor gene. DNA Cell Biol 22:253–259. doi: 10.1089/104454903321908647 PubMedCrossRefGoogle Scholar
  5. 5.
    Okegawa T, Li Y, Pong RC, Bergelson JM, Zhou J, Hsieh JT (2000) The dual impact of coxsackie and adenovirus receptor expression on human prostate cancer gene therapy. Cancer Res 60:5031–5036PubMedGoogle Scholar
  6. 6.
    Okegawa T, Pong RC, Li Y, Bergelson JM, Sagalowsky AI, Hsieh JT (2001) The mechanism of the growth-inhibitory effect of coxsackie and adenovirus receptor (CAR) on human bladder cancer: a functional analysis of car protein structure. Cancer Res 61:6592–6600PubMedGoogle Scholar
  7. 7.
    Sachs MD, Rauen KA, Ramamurthy M, Dodson JL, De Marzo AM, Putzi MJ et al (2002) Integrin alpha(v) and coxsackie adenovirus receptor expression in clinical bladder cancer. Urology 60:531–536. doi: 10.1016/S0090-4295(02)01748-X PubMedCrossRefGoogle Scholar
  8. 8.
    Kim M, Sumerel LA, Belousova N, Lyons GR, Carey DE, Krasnykh V et al (2003) The coxsackievirus and adenovirus receptor acts as a tumour suppressor in malignant glioma cells. Br J Cancer 88:1411–1416. doi: 10.1038/sj.bjc.6600932 PubMedCrossRefGoogle Scholar
  9. 9.
    Zhang LL, He DL, Li X, Li L, Zhu GD, Zhang D et al (2007) Overexpression of coxsackie and adenovirus receptor inhibit growth of human bladder cancer cell in vitro and in vivo. Acta Pharmacol Sin 28:895–900. doi: 10.1111/j.1745-7254.2007.00574.x PubMedCrossRefGoogle Scholar
  10. 10.
    Martin TA, Watkins G, Jiang WG (2005) The coxsackie-adenovirus receptor has elevated expression in human breast cancer. Clin Exp Med 5:122–128. doi: 10.1007/s10238-005-0076-1 PubMedCrossRefGoogle Scholar
  11. 11.
    Reimer D, Steppan I, Wiedemair A, Concin N, Hofstetter G, Marth C et al (2007) Soluble isoforms but not the transmembrane form of coxsackie-adenovirus receptor are of clinical relevance in epithelial ovarian cancer. Int J Cancer 120:2568–2575. doi: 10.1002/ijc.22580 PubMedCrossRefGoogle Scholar
  12. 12.
    You Z, Fischer DC, Tong X, Hasenburg A, Aguilar-Cordova E, Kieback DG (2001) Coxsackievirus-adenovirus receptor expression in ovarian cancer cell lines is associated with increased adenovirus transduction efficiency and transgene expression. Cancer Gene Ther 8:168–175. doi: 10.1038/sj.cgt.7700284 PubMedCrossRefGoogle Scholar
  13. 13.
    Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ et al (2007) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 25:118–145. doi: 10.1200/JCO.2006.09.2775 PubMedCrossRefGoogle Scholar
  14. 14.
    Cordera F, Jordan VC (2006) Steroid receptors and their role in the biology and control of breast cancer growth. Semin Oncol 33:631–641. doi: 10.1053/j.seminoncol.2006.08.020 PubMedCrossRefGoogle Scholar
  15. 15.
    Ikeda K, Inoue S (2004) Estrogen receptors and their downstream targets in cancer. Arch Histol Cytol 67:435–442. doi: 10.1679/aohc.67.435 PubMedCrossRefGoogle Scholar
  16. 16.
    Reimer D, Sadr S, Wiedemair A, Concin N, Hofstetter G, Marth C et al (2006) Heterogeneous cross-talk of E2F family members is crucially involved in growth modulatory effects of interferon-gamma and EGF. Cancer Biol Ther 5:771–776PubMedGoogle Scholar
  17. 17.
    Lippman ME, Dickson RB, Gelmann EP, Rosen N, Knabbe C, Bates S et al (1987) Growth regulation of human breast carcinoma occurs through regulated growth factor secretion. J Cell Biochem 35:1–16. doi: 10.1002/jcb.240350102 PubMedCrossRefGoogle Scholar
  18. 18.
    Morena AM, Oshima CT, Gebrim LH, Egami MI, Silva MR, Segreto RA et al (2004) Early nuclear alterations and immunohistochemical expression of Ki-67, Erb-B2, vascular endothelial growth factor (VEGF), transforming growth factor (TGF-beta1) and integrine-linked kinase (ILK) two days after tamoxifen in breast carcinoma. Neoplasma 51:481–486PubMedGoogle Scholar
  19. 19.
    Pong RC, Roark R, Ou JY, Fan J, Stanfield J, Frenkel E et al (2006) Mechanism of increased coxsackie and adenovirus receptor gene expression and adenovirus uptake by phytoestrogen and histone deacetylase inhibitor in human bladder cancer cells and the potential clinical application. Cancer Res 66:8822–8828. doi: 10.1158/0008-5472.CAN-05-4672 PubMedCrossRefGoogle Scholar
  20. 20.
    Sun JM, Chen HY, Davie JR (2001) Effect of estradiol on histone acetylation dynamics in human breast cancer cells. J Biol Chem 276:49435–49442. doi: 10.1074/jbc.M108364200 PubMedCrossRefGoogle Scholar
  21. 21.
    Dorner A, Xiong D, Couch K, Yajima T, Knowlton KU (2004) Alternatively spliced soluble coxsackie-adenovirus receptors inhibit coxsackievirus infection. J Biol Chem 279:18497–18503. doi: 10.1074/jbc.M311754200 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • Doris Auer
    • 1
  • Daniel Reimer
    • 1
  • Verena Porto
    • 1
  • Martina Fleischer
    • 1
  • Julia Roessler
    • 1
  • Annemarie Wiedemair
    • 1
  • Christian Marth
    • 1
  • Elisabeth Müller-Holzner
    • 1
  • Günter Daxenbichler
    • 1
  • Alain G. Zeimet
    • 1
    Email author
  1. 1.Department of Obstetrics and GynecologyInnsbruck Medical UniversityInnsbruckAustria

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