Oncogenic Wnt/β-catenin signalling pathways in the cancer-resistant epididymis have implications for cancer research.

Aberrant activation of the Wnt/β-catenin pathway occurs in cancers. This review presents several important cancer-related aspects of Wnt/β-catenin signalling relevant to the epididymis, provides evidence of such epididymal gene expression and suggests a new direction for further research. The data presented here indicate that besides containing many Wnt/β-catenin-pathway components, the normal adult human epididymis expresses much more β-catenin than the colorectal carcinoma cell line HCT116, which possesses elevated β-catenin expression. The low cancer incidence in the epididymis may be due to factors present in the human epididymis that regulate this oncogenic Wnt/β-catenin pathway, including (i) 14 of 17 secreted pathway inhibitors, (ii) the majority of the micro-RNAs known to target this pathway, (iii) plasma membrane-associated E-cadherin and CEACAM1 that anchor β-catenin, preventing its availability for nuclear entry and oncogenic transcriptional activity, (iv) the recently identified membrane-located tumourigenesis inhibitors RNF43 and ZNRF3 that mediate the degradation of the Wnt receptor components Fzds and Lrp5/6 and (v) nuclear KLF4, which competes with TCF for β-catenin, limiting its transcriptional activity and stabilizing telomeres, thereby reducing mutation incidence. The above regulatory factors expressed by the human epididymis, and the absence of androgen receptor translocation known to promote nuclear translocation of β-catenin in tumourigenesis in an animal model, may act synergistically to provide hostility in different cell compartments towards tumour formation. The lack of evidence for β-catenin in epididymal nuclei is noteworthy. Studying this phenomenon may help reveal the mechanisms underlying oncogenic Wnt/β-catenin signalling and shed new light on cancer therapy and prevention.