Skip to main content

Advertisement

SpringerLink
Log in

Physiological stress induces the metastasis marker AGR2 in breast cancer cells

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

As an approach to understanding the factors that activate expression of tumor progression genes, the role of physiological stress in the activation of a panel of tumor cell markers was investigated. These studies identify the developmental gene product, anterior gradient 2 (AGR2) as a cancer cell marker specifically up-regulated in response to depletion of serum and oxygen. AGR2 has been identified as a tumor marker in primary and secondary cancer lesions, and as a marker for detection of circulating tumor cells (CTCs). Elevated levels of AGR2 are known to increase the metastatic potential of cancer cells, but conditions leading to increased expression of AGR2 are not well understood. The present results identify novel physiological parameters likely to contribute to AGR2 induction in situ.

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

References

  1. Martin KJ, Kritzman BM, Price LM et al (2000) Linking gene expression patterns to therapeutic groups in breast cancer. Cancer Res 60:2232–2238

    PubMed  CAS  Google Scholar 

  2. Smirnov DA, Zweitzig DR, Foulk BW et al (2005) Global gene expression profiling of circulating tumor cells. Cancer Res 65:4993–4997

    Article  PubMed  CAS  Google Scholar 

  3. Risinger JI, Maxwell GL, Chandramouli GV et al (2003) Microarray analysis reveals distinct gene expression profiles among different histologic types of endometrial cancer. Cancer Res 63:6–11

    PubMed  CAS  Google Scholar 

  4. Huber M, Bahr I, Kratzschmar JR et al (2004) Comparison of proteomic and genomic analyses of the human breast cancer cell line T47D and the antiestrogen-resistant derivative T47D-r. Mol Cell Proteomics 3:43–55

    Article  PubMed  CAS  Google Scholar 

  5. Pohler E, Craig AL, Cotton J et al (2004) The Barrett’s antigen anterior gradient-2 silences the p53 transcriptional response to DNA damage. Mol Cell Proteomics 3:534–547

    Article  PubMed  CAS  Google Scholar 

  6. Liu D, Rudland PS, Sibson DR et al (2005) Human homologue of cement gland protein, a novel metastasis inducer associated with breast carcinomas. Cancer Res 65:3796–3805

    Article  PubMed  CAS  Google Scholar 

  7. Zhang JS, Gong A, Cheville JC et al (2005) AGR2, an androgen-inducible secretory protein overexpressed in prostate cancer. Genes Chromosomes Cancer 43:249–259

    Article  PubMed  CAS  Google Scholar 

  8. Aberger F, Weidinger G, Grunz H, Richter K (1998) Anterior specification of embryonic ectoderm: the role of the Xenopus cement gland-specific gene XAG-2. Mech Dev 72:115–130

    Article  PubMed  CAS  Google Scholar 

  9. Izuishi K, Kato K, Ogura T et al (2000) Remarkable tolerance of tumor cells to nutrient deprivation: possible new biochemical target for cancer therapy. Cancer Res 60:6201–6207

    PubMed  CAS  Google Scholar 

  10. Baek JH, Jang JE, Kang CM et al (2000) Hypoxia-induced VEGF enhances tumor survivability via suppression of serum deprivation-induced apoptosis. Oncogene 19:4621–4631

    Article  PubMed  CAS  Google Scholar 

  11. Bao S, Ouyang G, Bai X et al (2004) Periostin potently promotes metastatic growth of colon cancer by augmenting cell survival via the Akt/PKB pathway. Cancer Cell 5:329–339

    Article  PubMed  CAS  Google Scholar 

  12. Le QT, Denko NC, Giaccia AJ (2004) Hypoxic gene expression and metastasis. Cancer Metastasis Rev 23:293–310

    Article  PubMed  CAS  Google Scholar 

  13. Liotta LA, Kohn E (2004) Anoikis: cancer and the homeless cell. Nature 43:973–974

    Article  Google Scholar 

  14. Lee PD, Sladek R, Greenwood CM, Hudson TJ (2002) Control genes and variability: absence of ubiquitous reference transcripts in diverse mammalian expression studies. Genome Res 12:292–297

    Article  PubMed  Google Scholar 

  15. Knowles HJ, Harris AL (2001) Hypoxia and oxidative stress in breast cancer. Hypoxia and tumorigenesis. Breast Cancer Res 3:318–322

    Article  PubMed  CAS  Google Scholar 

  16. Pugh CW, Gleadle J, Maxwell PH (2001) Hypoxia and oxidative stress in breast cancer. Hypoxia signaling pathways. Breast Cancer Res 3:313–317

    Article  PubMed  CAS  Google Scholar 

  17. Rak J, Yu JL (2004) Oncogenes and tumor angiogenesis: the question of vascular “supply” and vascular “demand”. Semi Cancer Biol 14:93–104

    Article  CAS  Google Scholar 

  18. Chung J, Yoon S, Datta K et al (2004) Hypoxia-induced vascular endothelial growth factor transcription and protection from apoptosis are dependent on alpha-6-beta-1 integrin in breast carcinoma cells. Cancer Res 64:4711–4716

    Article  PubMed  CAS  Google Scholar 

  19. Gupta K, Kshirsagar S, Li W et al (1999) VEGF prevents apoptosis of human microvascular endothelial cells via opposing effects on MAPK/ERK and SAPK/JNK signaling. Exp Cell Res 247:495–504

    Article  PubMed  CAS  Google Scholar 

  20. Marenholz I, Heizmann CW (2004) S100A16, a ubiquitously expressed EF-hand protein which is up-regulated in tumors. Biochem Biophys Res Commun 313:237–244

    Article  PubMed  CAS  Google Scholar 

  21. Thompson DA, Weigel RJ (1998) hAG-2, the human homologue of the Xenopus laevis cement gland gene XAG-2, is coexpressed with estrogen receptor in breast cancer cell lines. Biochem Biophys Res Commun 251:111–116

    Article  PubMed  CAS  Google Scholar 

  22. Fletcher GC, Patel S, Tyson K et al (2003) hAG-2 and hAG-3, human homologues of genes involved in differentiation, are associated with oestrogen receptor-positive breast tumors and interact with metastasis gene C4.4a and dystroglycan. Br J Cancer 88:579–585

    Article  PubMed  CAS  Google Scholar 

  23. Innes HE, Liu D, Barraclough R et al (2006) Significance of the metastasis-inducing protein AGR2 for outcome in hormonally treated breast cancer patients. Br J Cancer 94:1057–1065

    Article  PubMed  CAS  Google Scholar 

  24. Parl FF (2003) Multiple mechanisms of estrogen receptor gene repression contribute to ER-negative breast cancer. Pharmacogenomics J 3:251–253

    Article  PubMed  CAS  Google Scholar 

  25. Yio X, Zhang JY, Babyatsky M et al (2005) Trefoil factor family-3 is associated with aggressive behavior of colon cancer cells. Clin Exp Metastasis 22:157–165

    Article  PubMed  CAS  Google Scholar 

  26. Rodrigues LR, Teixeira JA, Schmitt FL et al (2007) The role of osteopontin in tumor progression and metastasis in breast cancer. Cancer Epidemiol Biomarkers Prev 16:1087–1097

    Article  PubMed  CAS  Google Scholar 

  27. Harris AL (2002) Hypoxia—a key regulatory factor in tumor growth. Nat Rev Cancer 2:38–47

    Article  PubMed  CAS  Google Scholar 

  28. Liotta LA, Kohn EC (2001) The microenvironment of the tumor–host interface. Nature 411:375–379

    Article  PubMed  CAS  Google Scholar 

  29. Pennacchietti S, Michieli P, Galluzzo Mazzone MM et al (2003) Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 3:347–361

    Article  PubMed  Google Scholar 

  30. Persson S, Rosenquist M, Knoblach B et al (2005) Diversity of the protein disulfide isomerase family: identification of breast tumor induced Hag2 and Hag3 as novel members of the protein family. Mol Phylogenet Evol 36:734–740

    Article  PubMed  CAS  Google Scholar 

  31. Wilson CL, Sims AH, Howell A et al (2006) Effects of oestrogen on gene expression in epithelium and stroma of normal human breast tissue. Endocr Relat Cancer 13:617–628

    Article  PubMed  CAS  Google Scholar 

  32. Ostrakhovitch EA, Cherian MG (2005) Inhibition of extracellular signal regulated kinase (ERK) leads to apoptosis inducing factor (AIF) mediated apoptosis in epithelial breast cancer cells: the lack of effect of ERK in p53 mediated copper induced apoptosis. J Cell Biochem 95:1120–1134

    Article  PubMed  CAS  Google Scholar 

  33. Risbud MV, Fertala J, Vresilovic EJ et al (2005) Nucleus pulposus cells upregulate PI3K/Akt and MEK/ERK signaling pathways under hypoxic conditions and resist apoptosis induced by serum withdrawal. Spine 30:882–889

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We are grateful to Dr. Danny Dhanasekaran for the gift of the inhibitor compounds.

This work was supported by Dept. of Defense BCRP Grant # DAMD17–01-1-0406 to EM, and by Immunicon Corporation.

Author information

Authors and Affiliations

  1. Temple University School of Medicine, Fels Institute for Cancer Research, Philadelphia, PA, 19140, USA

    Daniel R. Zweitzig & Elizabeth Moran

  2. Immunicon Corporation, Huntingdon Valley, PA, 19006, USA

    Denis A. Smirnov, Mark C. Connelly, Leon W. M. M. Terstappen & S. Mark O’Hara

Authors
  1. Daniel R. Zweitzig
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Denis A. Smirnov
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mark C. Connelly
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Leon W. M. M. Terstappen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. Mark O’Hara
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Elizabeth Moran
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Elizabeth Moran.

Additional information

Daniel R. Zweitzig and Denis A. Smirnov contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zweitzig, D.R., Smirnov, D.A., Connelly, M.C. et al. Physiological stress induces the metastasis marker AGR2 in breast cancer cells. Mol Cell Biochem 306, 255–260 (2007). https://doi.org/10.1007/s11010-007-9562-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-007-9562-y

Keywords

Search

Navigation