Nuclear localization and increased levels of transcription factor YB-1 in primary human breast cancers are associated with intrinsic MDR1 gene expression (original) (raw)

Nature Medicine volume 3, pages 447–450 (1997)Cite this article

Abstract

Breast cancers are either primarily resistant to chemotherapy (intrinsic resistance), or respond to chemotherapy but later recur with a multidrug-resistant phenotype because of overexpression of the multidrug transporter P-glycoprotein1. The MDR1 gene encoding P-glycoprotein may be transcriptionaily regulated by a Y-box transcription factor2. We now report that, in multidrug-resistant MCF-7 breast cancer cells, nuclear localization of YB-1 is associated with MDR-1 gene expression. In drug-sensitive MCF-7 cells, however, YB-1 was localized to the cytoplasm. Regulated overexpression of YB-1 in drug-sensitive diploid breast epithelial cells induced MDR-1 gene expression and multidrug resistance. In 27 out of 27 untreated primary breast cancers, YB-1 protein was expressed in the cytoplasm although it was undetectable in normal breast tissue of these patients. In a subgroup of tumors (9/27), however, YB-1 was also localized to the nucleus and, in these cases, high levels of P-glycoprotein were present. These results show that in a subset of untreated primary breast cancers, nuclear localization of YB-1 protein is associated with intrinsic multidrug resistance. Our data show that YB-1 has an important role in controlling MDR1 gene transcription and this finding provides a basis for the analysis of molecular mechanisms responsible for intrinsic multidrug resistance in human breast cancer.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 12 print issues and online access

$209.00 per year

only $17.42 per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

References

  1. Gottesman, M.M. & Pastan, I. Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu. Rev. Biochem. 62, 385–427 (1993).
    Article CAS Google Scholar
  2. Goldsmith, M.E., Madden, M.J., Morrow, C.S. & Cowan, K.H. A Y-box consensus sequence is required for basal expression of the human multidrug resistance (MDR1) gene. J. Biol. Chem. 268, 5856–5860 (1993).
    CAS PubMed Google Scholar
  3. Verelle, P. et al. Clinical relevance of immunohistochemical detection of multidrug resistance P-glycoprotein in breast carcinoma. J. Natl. Cancer Inst. 83, 111–116 (1991).
    Article Google Scholar
  4. Schneider, J. et al. P-glycoprotein, HER-2/neu and mutant p53 expression in human gynecologic tumors. J. Natl. Cancer Inst. 86, 850–855 (1994).
    Article CAS Google Scholar
  5. Madden, M.J. et al. Identification of 5′ and 3′ sequences involved in the regulation of transcription of the human MDR1 gene in vivo. J. Biol. Chem. 268, 8209–8297 (1993).
    Google Scholar
  6. van Groeningen, M., Valentijn, L.J. & Baas, F. Identification of a functional initiator sequence in the human MDR1 promoter. Biochim. Biophys. Acta 1172, 138–146 (1993).
    Article Google Scholar
  7. Wolffe, A.P. Structural and functional properties of the evolutionary ancient Y-box family of nucleic acid binding proteins. BioEssays 16, 245–251 (1994).
    Article CAS Google Scholar
  8. Ladomery, M. & Sommerville, J. A role for Y-box proteins in cell proliferation. BioEssays 17, 9–11 (1995).
    Article CAS Google Scholar
  9. Asakuno, K. et al. Involvement of a DNA binding protein, MDR-NFY/YB-1, in human MDR1 gene expression by actinomycin D. Bochem. Biophys. Res. Commun. 199, 1428–1435 (1994)
    Article CAS Google Scholar
  10. Gossen, M. & Bujard, H. Tight control of gene expression in mammalian cells by tetracycline responsive promoters. Proc. Natl. Acad. Sci. USA 89, 5547–5551 (1992)
    Article CAS Google Scholar
  11. Bittl, A., Nap, M., Jäger, W., Cornillie, F. & Lang, N. Immunohistochemical detection of P-glycoprotein on frozen and paraffin-embedded tissue sections of normal and malignant tissues. Anticancer Res. 15, 1007–1014 (1995).
    CAS PubMed Google Scholar
  12. Sanfilippo, O., Ronchi, E., De-Marco, C., Di-Fronzo, G. & Silvestrini, R. Expression of P-glycoprotein in breast cancer tissue and in vitro resistance to doxorubicin and vincristine. Eur J. Cancer 27, 155–158 (1991).
    Article CAS Google Scholar
  13. Pinedo, H.M. & Giaccone, G., P-glycoprotein — a marker of cancer-cell behavior. New Engl. J. Med. 333, 1417–1419 (1995).
    Article CAS Google Scholar
  14. Lee, C.H., Bradley, G. & Ling, V. Expression of P-glycoprotein in normal and malignant rat liver cells. Cold Spring Harbor Symp. Quant. Biol. 59, 607–615 (1994).
    Article CAS Google Scholar
  15. Weinstein, R.S. et al. Relationship of the expression of the multidrug resistance gene product (P-glycoprotein) in human colon carcinoma to local tumor aggressiveness and lymph node metastasis. Cancer Res. 51, 2720–2726 (1991).
    CAS PubMed Google Scholar
  16. Baldini, N. et al. Expression of P-glycoprotein in high-grade osteosarcomas in relation to clinical outcome. New Engl. J. Med. 333, 1380–1385 (1995).
    Article CAS Google Scholar
  17. Spitkovsky, D.D. et al. Tissue restricted expression and chromosomal localization of the YB-1 gene encoding a 42kD nuclear CCAAT binding protein. Nucleic Acids Res. 20, 797–803 (1992).
    Article CAS Google Scholar
  18. Bargou, R.C. et al. Overexpression of the death-promoting gene bax-alpha which is downregulated in breast cancer restores sensitivity to different apoptotic stimuli and reduces tumor growth in SCID mice. J. Clin. Invest. 97, 2651–2659 (1996).
    Article CAS Google Scholar
  19. Grinstein, E., Weinert, I., Pagano, M., Droese, B. & Royer, H.-D. Cell cycle regulation of nuclear factor p92 DNA-binding activity by novel phase-specific inhibitors. J. Biol. Chem. 271, 9215–9222 (1996).
    Article CAS Google Scholar
  20. Royer, H.-D. et al. Delineation of human papillomavirus type 18 enhancer binding proteins: The intra cellular distribution of a novel octamer binding protein p92 is Cell cycle regulated. Nucleic Acids Res. 19, 2363–2371 (1991).
    Article CAS Google Scholar

Download references

Author information

Authors and Affiliations

  1. Humboldt Universität zu Berlin, Universitätsklinikum Rudolf Virchow, Robert-Rössle Klinik, Robert-Rössle Strasse 10, 13122, Berlin, Germany
    Ralf C. Bargou, Karsten Jürchott, Christian Wagener, Stephan Bergmann, Kurt Bommert, Markus Y. Mapara, Bernd Dörken & Hans-Dieter Royer
  2. Max-Delbrück Centrum für Molekulare Medizin, Robert-Rössle Strasse 10, 13122, Berlin, Germany
    Ralf C. Bargou, Sylvia Metzner, Markus Y. Mapara, Bernd Dörken & Hans-Dieter Royer
  3. Institut für Pathologie, Universitätsklinikum Charité, Humboldt-Universität zu Berlin, Schumannstrasse 20-21, 10117, Berlin, Germany
    Manfred Dietel
  4. Chirurgie, Universitätsklinikum Charité, Humboldt-Universität zu Berlin, Schumannstrasse 20-21, 10117, Berlin, Germany
    Klaus-Jürgen Winzer

Authors

  1. Ralf C. Bargou
    You can also search for this author inPubMed Google Scholar
  2. Karsten Jürchott
    You can also search for this author inPubMed Google Scholar
  3. Christian Wagener
    You can also search for this author inPubMed Google Scholar
  4. Stephan Bergmann
    You can also search for this author inPubMed Google Scholar
  5. Sylvia Metzner
    You can also search for this author inPubMed Google Scholar
  6. Kurt Bommert
    You can also search for this author inPubMed Google Scholar
  7. Markus Y. Mapara
    You can also search for this author inPubMed Google Scholar
  8. Klaus-Jürgen Winzer
    You can also search for this author inPubMed Google Scholar
  9. Manfred Dietel
    You can also search for this author inPubMed Google Scholar
  10. Bernd Dörken
    You can also search for this author inPubMed Google Scholar
  11. Hans-Dieter Royer
    You can also search for this author inPubMed Google Scholar

Rights and permissions

About this article

Cite this article

Bargou, R., Jürchott, K., Wagener, C. et al. Nuclear localization and increased levels of transcription factor YB-1 in primary human breast cancers are associated with intrinsic MDR1 gene expression.Nat Med 3, 447–450 (1997). https://doi.org/10.1038/nm0497-447

Download citation

This article is cited by