Expression Patterns of the Wnt Pathway Inhibitors Dickkopf3 and Secreted Frizzled-Related Proteins 1 and 4 in Endometrial Endometrioid Adenocarcinoma: An NRG Oncology/Gynecologic Oncology Group Study

Int J Gynecol Cancer. 2016 Jan;26(1):125-32. doi: 10.1097/IGC.0000000000000563.


Objective: The aim of the study was to determine the differential expression patterns of the wingless-type (Wnt) pathway inhibitors Dkk3 (Dickkopf 3), SFRP1 (secreted frizzled-related protein 1), and SFRP4 in normal müllerian tissue and endometrial endometrioid adenocarcinoma specimens.

Methods: Messenger RNA (mRNA) and protein levels of the Wnt pathway inhibitors Dkk3, SFRP1, and SFRP4 were evaluated by real-time reverse transcription-polymerase chain reaction and Western blot analysis. A total of 87 human tissue specimens were obtained from 60 women who participated in Gynecologic Oncology Group protocol 210. Twenty-seven normal müllerian tissues, 32 early-stage, and 28 advanced-stage endometrial endometrioid cancer specimens were analyzed.

Results: Median age for this cohort was 60 years, with median body mass index of 32 kg/m. There was a difference in Dkk3 protein expression between normal müllerian tissues and primary endometrial endometrioid adenocarcinoma samples (P = 0.05). There was down-regulation of Dkk3, SFRP1, and SFRP4 mRNA expression in patients with high-grade disease (P = 0.08, 0.06, and 0.05, respectfully). Furthermore, a decrease in SFRP1 and SFPR4 mRNA expression was noted in patients with a diagnosis of locoregional and distant disease recurrence. Lastly, a trend toward decreased progression-free survival in patients with low Dkk3, SFRP1, and SFRP4 mRNA expression levels was noted.

Conclusions: Wnt pathway inhibitor (Dkk3, sFRP1, and/or sFRP4) expression was down-regulated in patients with high-grade disease and was associated with locoregional and distant disease recurrence. Despite sample size (power) limitations, these results support previous preclinical studies and may suggest a therapeutic role for Wnt signaling in endometrial cancer.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Aged
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Blotting, Western
  • Carcinoma, Endometrioid / genetics*
  • Carcinoma, Endometrioid / metabolism
  • Carcinoma, Endometrioid / pathology
  • Chemokines
  • Cohort Studies
  • Endometrial Neoplasms / genetics*
  • Endometrial Neoplasms / metabolism
  • Endometrial Neoplasms / pathology
  • Female
  • Follow-Up Studies
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Middle Aged
  • Neoplasm Grading
  • Neoplasm Recurrence, Local / genetics*
  • Neoplasm Recurrence, Local / metabolism
  • Neoplasm Recurrence, Local / pathology
  • Neoplasm Staging
  • Prognosis
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Survival Rate
  • Tumor Cells, Cultured
  • Wnt Signaling Pathway


  • Adaptor Proteins, Signal Transducing
  • Biomarkers, Tumor
  • Chemokines
  • DKK3 protein, human
  • Intercellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • SFRP1 protein, human
  • SFRP4 protein, human