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.

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/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.

• Authors: Ramez N Eskander, Shamshad Ali, Thanh Dellinger, Heather A Lankes, Leslie M Randall, Nilsa C Ramirez, Bradley J Monk, Joan L Walker, Eric Eisenhauer, Bang H Hoang
• Journal: International journal of gynecological cancer : official journal of the International Gynecological Cancer Society (Int J Gynecol Cancer) Vol. 26 Issue 1 Pg. 125-32 (Jan 2016) ISSN: 1525-1438 [Electronic] England
• PMID: 26397159 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural)

Chemical References

• 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

Topics

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