Breast Cancer Research and Treatment

, Volume 112, Issue 2, pp 263–273 | Cite as

Dickkopf-1 mediated tumor suppression in human breast carcinoma cells

  • Andrei M. Mikheev
  • Svetlana A. Mikheeva
  • John-Patrick Maxwell
  • Julia V. Rivo
  • Robert Rostomily
  • Karen Swisshelm
  • Helmut Zarbl
Preclinical Study


Dickkopf-1 (DKK-1) is a secreted inhibitor of the Wnt signaling pathway. We previously identified DKK-1 as a candidate tumor suppressor and demonstrated that ectopic expression of the DKK-1 suppressed the tumorigenicity of HeLa cells in vitro and in vivo. Since suppression of tumorigenicity of HeLa cells by DKK-1 overexpression was not mediated by effects on β-catenin dependent transcription, we hypothesized that DKK-1 might also inhibit tumorigenicity of breast carcinoma cell lines lacking an activated canonical Wnt pathway. In the present study we show that ectopic expression of DKK-1 in various breast cancer cell lines resulted in a change in the cell phenotype, increased sensitivity to apoptosis, inhibition of anchorage independent growth in vitro, and suppression of tumorigenicity in vivo. Consistent with known effects of DKK-1 on the canonical Wnt signaling pathway, ectopic expression of DKK-1 in breast carcinoma cells was associated with increased phosphorylation and degradation of β-catenin. However, none of the breast tumor cells used in this study showed detectable levels of β-catenin dependent activation of TCF/Lef promoter activity measured by reporter constructs. Consistent with the results of these transient transfection assays, we were unable to demonstrate the expected β-catenin dependent, TCF/Lef mediated inhibition of cyclin D1 and c-myc gene transcription in breast cells overexpressing DKK-1. However, we found that cells with DKK-1 overexpression have increased activity of CamKII pathway. Overexpression of the constitutively active form of CamKII (T286D) resulted in inhibition of breast cancer cell tumorigenicity. Thus, our study supports the hypothesis that DKK-1 mediated tumor suppressor effect is independent of β-catenin dependent transcription and identified the CamKII pathway that contributes into DKK-1 signaling.


Tumor suppressor Breast cancer Dickkopf-1 CamKII Nude mice Soft agar β-catenin 



We thank Dr. Randall Moon for valuable discussion. This research was supported by Public Health Services, with NIH grants to the NIEHS sponsored FHCRC/UW Toxicogenomics Research Consortium, Grant # NIEHS U19ES011387, and the NIEHS sponsored UW Center for Ecogenetics and Environmental Health, Grant #: NIEHS P30ES07033, by an IDEA grant from the U.S. Army Medical Research and Materiel Command, Grant # DAMD17-98-1-8086 and NIH/NINDS training grant NS0007144. J.V.R. is supported by the University of Washington Anesthesiology Departmental Research Fund.

Supplementary material

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Copyright information

© Springer Science+Business Media, LLC. 2007

Authors and Affiliations

  • Andrei M. Mikheev
    • 1
    • 2
  • Svetlana A. Mikheeva
    • 1
  • John-Patrick Maxwell
    • 1
  • Julia V. Rivo
    • 3
  • Robert Rostomily
    • 1
  • Karen Swisshelm
    • 4
  • Helmut Zarbl
    • 2
    • 5
  1. 1.Department of Neurological SurgeryUniversity of WashingtonSeattleUSA
  2. 2.Program in Cancer Biology, Divisions of Human Biology and Public HealthFred Hutchinson Cancer Research CenterSeattleUSA
  3. 3.Department of AnesthesiologyUniversity of WashingtonSeattleUSA
  4. 4.Department of PathologyUniversity of Colorado Denver and Health Sciences CenterDenverUSA
  5. 5.Environmental and Occupational Health Sciences Institute and Robert Wood Johnston Medical SchoolUniversity of Medicine and Dentistry of New Jersey and Rutgers UniversityPiscatawayUSA

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