Dickkopf-1 mediated tumor suppression in human breast carcinoma cells

Andrei M Mikheev, Svetlana A. Mikheeva, John Patrick Maxwell, Julia V. Rivo, Robert C. Rostomily, Karen Swisshelm, Helmut Zarbl

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)263-273
Number of pages11
JournalBreast Cancer Research and Treatment
Volume112
Issue number2
DOIs
StatePublished - Nov 1 2008

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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