Addressing activation of WNT beta-catenin pathway in diverse landscape of endometrial carcinogenesis

Abstract

The WNT-beta-catenin pathway (WP) is one of the major oncogenic pathways in solid tumors. Wnt beta-catenin pathway plays a unique role in a wide range of endometrial dysfunctions, from embryo implantation failure to severe pathogenic changes like endometriosis and endometrial cancer. Although abnormal activation of the pathway has long been known to be associated with endometrial tumorigenesis, the pathway's exact mode of involvement remains to be understood. As more evidence has been presented in favor of a crucial role of the WP in solid tumors, including endometrial cancer, anti-WP drugs are currently being tested to manage the disease. Aggressive tumor cells are nurtured by the tumor microenvironment (TME). The genetic alterations within tumor cells are the primary driving force to activate the extra-tumoral micro-environment. TME (a) provides metabolic support for the proliferation of tumor cells, (b) orchestrates immune-evasion, (c) initiates mechanistic signaling for several metastasis-associated phenotypes, and (d) supports cellular events for the development of drug resistance. To get metabolic as well as immune support from the tumor microenvironment, tumor cells cross-talk with components of the TME, most critically to the cancer-associated fibroblasts. Thus it is expected that the tumor-TME cross-talk throughout the process of tumorigenesis and metastasis is one of the characteristic features of an aggressive tumor. Here we review the WP's mechanistic involvement as a common culprit (Un Colpevole Comune) in endometrial tumor cells and endometrial cancer-associated fibroblast (CAF). In this review, we have attempted to discuss the activation of the WP in the genesis and progression of endometrial cancers, including endometrial tumor biology, tumor microenvironment, cancer-associated fibroblasts, and wnt-beta catenin genetic alteration. We interrogated the available literature on the various aspects of endometrial carcinogenesis leading to the pathway's activation. We examined how genetic alterations in WP directly influence tumor cell signaling to bring out different tumor cell phenotypes, and present palpable evidence to envision a role of WP inhibitors in the future management of the disease.

Keywords: Wnt beta-catenin pathway; cancer-associated fibroblasts; cell signaling; tumor cells.

Figure 1

Modes and mediators of WP activation of beta-catenin in endometrial cancers: The WP pathway has multiple identified regulatory mechanisms in addition to the phosphorylation and ubiquitination of beta-catenin protein. Thus several mechanisms of dysregulation-mediated WP hyperactivation have been identified, which are responsible for the oncogenesis of various cancers, including endometrial cancers. The dysregulation of the WP pathway is mediated through different modes involving alterations of different genes, miRNAs, transcription factors, proteins, inhibitors, and antagonists.

Figure 2

Hotspot mutations of Beta-catenin and events at the “death box” of beta-catenin in Endometrial Cancers: Mutations of beta-catenin were so far identified as a single missense mutation(s) on serine/threonine residues (residues 33, 37, 41, and 45 as well as 32 and 34) within exon 3. The sites at 33, 37, and 41 are the consensus phosphorylation sites for GSK3beta binding, altering the GSK3beta mediated phosphorylation of the beta-catenin. The site at 44 is the phosphorylation site for casein kinase 1. The phosphorylation(s) at the above positions are necessary for the initiation of degradation of beta-catenin within its “death box”. Sites 32 and 34 are the essential site for the interaction of beta-catenin with FBW1. FBW1 interacts with p300 to enhance the transcriptional activity of beta-catenin in the nucleus. Mutation sites (hotspot) of the CTNNB1 gene and the events at the “death box” of beta-catenin are presented (upper panel). Activated AKT phosphorylates GSK3beta and thus inactivates it. Phosphorylated/inactivated GSK3beta fails to initiate ubiquitin-mediated degradation of beta-catenin in the “death box” involving AXIN1 and APC. Casein kinase-1 (CK1) initially phosphorylates beta-catenin at Ser 45, which induces the sequential phosphorylation of beta-catenin at Ser 33, 37, and T41 by GSK3beta. Following serine/threonine phosphorylation, beta-catenin is recognized and degraded by E3 ubiquitin ligase. The resulting increase in beta-catenin levels in the nucleus causes the transcriptional activation of beta-catenin target genes. Drugs that blocked the activation of AKT perturbs WP (lower panel).

Figure 3

Alterations of the WP genes in patients with endometrial cancers: The Avera Experience: Alterations of the WP genes in patients with endometrial cancers from Avera Cancer Institute are presented. The data (FoundationOne reports) were obtained from 82 tumor samples from patients with endometrial cancers. The figure shows the number of alterations of the genes of the “death box” of beta-catenin.

Figure 4

Hotspot mutations of CTNNB1 gene in patients with endometrial cancers: The avera experience: hotspot mutations were observed at different locations of the beta-catenin gene in tumors from patients with endometrial cancers. Different locations on the beta-catenin gene are depicted as numbers. Two types of alterations of the beta-catenin gene, missense mutations and deletion mutations, were observed in patients’ tumors with our cohort. Numbers in the figure represent the positions of the alterations. All the above alterations occurred within the hotspot of the beta-catenin gene. While alterations at positions from 33 to 45 have been previously identified and reported earlier, the deletion mutations at Q28_S37 del has been observed for the first time in the cohort of endometrial patients from Avera.