Crosstalk of estrogen receptors and Wnt/β-catenin signaling in endometrial cancer

Purpose: To investigate the interaction between Wnt/β-catenin and estrogen signaling pathways in endometrial cancer (EC).

Methods: 119 women were involved in this study, including 65 women with histologically confirmed EC and 54 healthy women as a control group. Serum protein levels of Dkk1 were measured using ELISA. Protein expression levels of Dkk1, β-catenin, ER-β isoforms (β1, β2, β5), and ER-α were tested in paraffin-embedded tissues using IHC. Gene expression levels of Dkk1, CTNNB, ESR1, and ESR2 were tested in fresh tumorous and normal endometrium tissues using RT-PCR.

Results: EC patients had significantly higher serum levels of Dkk1 protein compared with healthy women. Dkk1 and β-catenin showed different expression pattern in tumor cells compared to it in normal cells at the protein level but not at the gene level. Protein expression levels of ERβ2 and ERα were significantly lower in tumor cells compared with tumor-adjacent normal cells. Increased protein expression levels of ERα were associated with favorable clinicopathological features and better overall survival rate (OS). Protein expression levels of ERα were correlated with protein expression levels of Dkk1 and cytoplasmic β-catenin. The association between ERα expression levels and OS was no more significant when tested in regard to Dkk1- and cytoplasmic β-catenin expression levels.

Conclusions: Our data demonstrated that Wnt/β-catenin and estrogen signaling systems are dysregulated in EC showing; for the first time, a potential crosstalk between certain components of these two pathways, which in turn has affected the specificity of these molecules in disease characteristics. Understanding the signaling networks in EC is crucial in designing clinical trials to evaluate the efficacy of molecular-targeted agents and providing more successful therapies in the future.