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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
  1. Ramez N. Eskander, MD*,
  2. Shamshad Ali, MA,
  3. Thanh Dellinger, MD,
  4. Heather A. Lankes, PhD, MPH,
  5. Leslie M. Randall, MD*,
  6. Nilsa C. Ramirez, MD§,
  7. Bradley J. Monk, MD,
  8. Joan L. Walker, MD,
  9. Eric Eisenhauer, MD# and
  10. Bang H. Hoang, MD**
  1. *Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of California, Irvine, Medical Center, Orange, CA;
  2. Gynecologic Oncology Group, Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY;
  3. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, City of Hope Comprehensive Cancer Center, Duarte, CA;
  4. §The Research Institute at Nationwide Children’s Hospital, Columbus, OH;
  5. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Arizona Cancer Center, Creighton University School of Medicine, St Joseph’s Hospital and Medical Center, Phoenix, AZ;
  6. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Oklahoma, Oklahoma City, OK;
  7. #Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Cincinnati College of Medicine, Cincinnati, OH; and
  8. **Department of Orthopedic Surgery, University of California, Irvine, Orange, CA.
  1. Address correspondence and reprint requests to Ramez N. Eskander, MD, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of California, Irvine, Medical Center, 101 The City Dr S, Bldg 56, Suite 260, Orange, CA 92868. E-mail: Eskander@uci.edu.

Abstract

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/m2. 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.

  • Dkk3
  • SFRP1
  • SFRP4
  • Uterine cancer
  • Wnt pathway

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Footnotes

  • B.J.M. is now with the Creighton University School of Medicine, Phoenix, AZ.

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