Presented are three casuistics of seemingly identical breast lesions which even by adopting advanced laboratory techniques may represent diagnostic challenge. Microscopic features of some bland spindle cell lesions of different histogenesis (epithelial or mesenchymal) are misleading and a potential source of unaware errors, which might affect optimal therapeutic strategy. In the setting of three diverse entities (low-grade spindle cell metaplastic carcinoma, desmoid fibromatosis and phyllodes tumor) is documented both demanding diagnostic algorithm and revealing molecular landscape on one side as well as evolving predictive/prognostic parameters on the other one. Close interdisciplinary cooperation is inevitable for accurate interpretation/understanding of revealed diagnostic facts which is required for adjustment of competent rational and individualized therapy.

Invasive lobular carcinoma (ILC) is the most common special type of invasive breast cancer (IBC), accounting for 5-15% of IBCs. The distinct histomorphology of ILC reflects a special tumor biology, the hallmark of which is the lack of E-cadherin expression. However, the occasional presence of E-cadherin expression and the presence of IBC of no special type (IBC, NST)-like morphologies in ILC and vice versa make the diagnosis challenging.  We present two cases of the alveolar variant of ILC, a diagnostically challenging entity. The first case is an 81-year-old female with two discrete right breast masses at 1 o\'clock and 9 o\'clock positions.  The second case is a 61-year-old female with two discrete left breast masses located at 11 o\'clock and 12 o\'clock positions. Core needle biopsies and subsequent mastectomy were performed in both cases. On histology, three tumor foci were identified in the first case. The 1 o\'clock focus showed IBC, NST, grade 3/3, ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS). The 9 o\'clock focus revealed ILC, classic and alveolar variants, grade 2/3, while a nearby third incidental focus was ILC, alveolar variant, both supported by lack of E-cadherin and β-catenin immunostaining.  The second case showed ILC, alveolar variant, grade 1 with LCIS component in the 11 o\'clock lesion on both biopsy and mastectomy specimens. The lesion at the 12 o\'clock position was diagnosed as IBC, NST, grade 2 with high-grade DCIS and LCIS components.  It is challenging to distinguish the alveolar variant of ILC from IBC, NST, and in situ lesions because of the overlapping morphology and occasional E-cadherin expression. Altered adherence of lobular cells may also be due to loss of α-, β-, and γ-catenins, and cytoplasmic re-localization of p120-catenin. Therefore, in ILC, the lack of β-catenin can be used as an adjunct along with E-cadherin. Myoepithelial markers such as p63 and smooth muscle myosin heavy chain (SMMHC) can be used to distinguish the alveolar variant of ILC from LCIS.

UNASSIGNED: Acute myeloid leukaemia (AML) is a disease of the haematopoietic stem cells(HSCs) that is characterised by the uncontrolled proliferation and impaired differentiation of normal haematopoietic stem/progenitor cells. Several pathways that control the proliferation and differentiation of HSCs are impaired in AML. Activation of the Wnt/beta-catenin signalling pathway has been shown in AML and beta-catenin, which is thought to be the key element of this pathway, has been frequently highlighted. The present study was designed to determine beta-catenin expression levels and beta-catenin-related genes in AML.
UNASSIGNED: In this study, beta-catenin gene expression levels were determined in 19 AML patients and 3 controls by qRT-PCR. Transcriptome analysis was performed on AML grouped according to beta-catenin expression levels. Differentially expressed genes(DEGs) were investigated in detail using the Database for Annotation Visualisation and Integrated Discovery(DAVID), Gene Ontology(GO), Kyoto Encyclopedia of Genes and Genomes(KEGG), STRING online tools.
UNASSIGNED: The transcriptome profiles of our AML samples showed different molecular signature profiles according to their beta-catenin levels(high-low). A total of 20 genes have been identified as hub genes. Among these, TTK, HJURP, KIF14, BTF3, RPL17 and RSL1D1 were found to be associated with beta-catenin and poor survival in AML. Furthermore, for the first time in our study, the ELOV6 gene, which is the most highly up-regulated gene in human AML samples, was correlated with a poor prognosis via high beta-catenin levels.
UNASSIGNED: It is suggested that the identification of beta-catenin-related gene profiles in AML may help to select new therapeutic targets for the treatment of AML.

Precise control of morphogen signaling levels is essential for proper development. An outstanding question is: what mechanisms ensure proper morphogen activity and correct cellular responses? Previous work has identified Semaphorin (SEMA) receptors, Neuropilins (NRPs) and Plexins (PLXNs), as positive regulators of the Hedgehog (HH) signaling pathway. Here, we provide evidence that NRPs and PLXNs antagonize Wnt signaling in both fibroblasts and epithelial cells. Further, Nrp1/2 deletion in fibroblasts results in elevated baseline Wnt pathway activity and increased maximal responses to Wnt stimulation. Notably, and in contrast to HH signaling, SEMA receptor-mediated Wnt antagonism is independent of primary cilia. Mechanistically, PLXNs and NRPs act downstream of Dishevelled (DVL) to destabilize β-catenin (CTNNB1) in a proteosome-dependent manner. Further, NRPs, but not PLXNs, act in a GSK3β/CK1-dependent fashion to antagonize Wnt signaling, suggesting distinct repressive mechanisms for these SEMA receptors. Overall, this study identifies SEMA receptors as novel Wnt pathway antagonists that may also play larger roles integrating signals from multiple inputs.

Postchemotherapy postpubertal-type yolk sac tumors (YST) with glandular and solid phenotypes are aggressive and commonly resistant to systemic chemotherapy. These neoplasms show morphologic features that significantly overlap with those of somatic carcinomas with \"enteroblastic\" or \"fetal\" phenotype (the preferred terminology depends on the site of origin). They often present as late or very late recurrences, and their diagnosis is challenging because they frequently affect patients in an age group at risk for carcinomas of somatic origin. Recently, we incidentally identified examples of postchemotherapy glandular and solid YST with \"enteroblastic\" phenotypes and nuclear expression of beta-catenin, prompting us to further evaluate the prevalence of this phenomenon. We found nuclear expression of beta-catenin in 10 (29%) of 34 such tumors. A subset of cases with nuclear beta-catenin expression was further analyzed with a DNA sequencing panel (n = 6) and fluorescence in situ hybridization for isochromosome 12p [i(12p); n = 5]. Sequencing identified exon 3 CTNNB1 variants in 3 (50%) of 6 analyzed cases, and fluorescence in situ hybridization was positive for i(12p) in 5 of 5 cases. In conclusion, a significant subset of postchemotherapy YST with glandular or solid architecture and \"enteroblastic\" phenotype demonstrates beta-catenin alterations, suggesting that activation of Wnt signaling may play a role in the progression of these neoplasms. Moreover, nuclear beta-catenin expression in these tumors represents a potential diagnostic pitfall given that carcinomas of true somatic origin with overlapping morphology may also be positive for this marker.

Mutations in the gene for β-catenin cause liver cancer cells to release fewer exosomes, which reduces the number of immune cells infiltrating the tumor.

The reprogramming of glutamine metabolism is a key event in cancer more generally and in hepatocellular carcinoma (HCC) in particular. Glutamine consumption supplies tumours with ATP and metabolites through anaplerosis of the tricarboxylic acid cycle, while glutamine production can be enhanced by the overexpression of glutamine synthetase. In HCC, increased glutamine production is driven by activating mutations in the CTNNB1 gene encoding β-catenin. Increased glutamine synthesis or utilisation impacts tumour epigenetics, oxidative stress, autophagy, immunity and associated pathways, such as the mTOR (mammalian target of rapamycin) pathway. In this review, we will discuss studies which emphasise the pro-tumoral or tumour-suppressive effect of glutamine overproduction. It is clear that more comprehensive studies are needed as a foundation from which to develop suitable therapies targeting glutamine metabolic pathways, depending on the predicted pro- or anti-tumour role of dysregulated glutamine metabolism in distinct genetic contexts.

OBJECTIVE: Nasopharyngeal carcinoma (NPC), a common cancer in Southern China, is associated with Epstein-Barr Virus (EBV) infection. Although many therapies for NPC have been established, the definite role of EBV in NPC remains unclear. Therefore, this work focuses on LMP2A, a latent EBV gene, and investigates whether LMP2A is related to peroxiredoxin 1 (PRDX1) in EBV-positive NPC.
METHODS: The mRNA and protein expression levels of LMP2A, PRDX1, and beta-catenin were compared in patient samples. To identify molecular mechanisms, EBV-negative NP69 and EBV-positive C666-1 NPC cell lines were used. After making an agar cell block for cell slides, the intensity of LMP2A expression was observed visually. To measure the level of reactive oxygen species, both fluorescence microscope and flow cytometry were used. To investigate the intracellular signaling molecular mechanisms with and without the LMP2A gene, reverse transcription polymerase chain reaction and western blotting were used.
RESULTS: Both patient samples and cells of nasopharyngeal carcinoma infected with EBV had increased expression of LMP2A compared with controls, and high ROS levels were identified. Cell viability assay showed that LMP2A promoted cell growth by regulating gene expression. Furthermore, LMP2A induced the expression of PRDX1 and beta-catenin. LMP2A also increased the expression of both cyclin B1 and cyclin D1.
CONCLUSIONS: In NPC cells, PRDX1 and beta-catenin were regulated through LMP2A expression, which reduced cell growth through cell cycle-related gene expression. This study suggests that LMP2A could be a target molecule for inhibiting cancer progression in NPC cells infected with EBV.

OBJECTIVE: To investigate the synergistic effects of polyphyllin I (PPI) combined with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on the growth of osteosarcoma cells through downregulating the Wnt/β-catenin signaling pathway.
METHODS: Cell viability, apoptosis and cell cycle distribution were examined using cell counting kit-8 and flow cytometry assays. The morphology of cancer cells was observed with inverted phase contrast microscope. The migration and invasion abilities were examined by xCELLigence real time cell analysis DP system and transwell assays. The expressions of poly (adenosine diphosphate-ribose) polymerase, C-Myc, Cyclin B1, cyclin-dependent kinases 1, N-cadherin, Vimentin, Active-β-catenin, β-catenin, p-glycogen synthase kinase 3β (GSK-3β) and GSK-3β were determined by Western blotting assay.
RESULTS: PPI sensitized TRAIL-induced decrease of viability, migration and invasion, as well as increase of apoptosis and cell cycle arrest of MG-63 and U-2 OS osteosarcoma cells. The synergistic effect of PPI with TRAIL in inhibiting the growth of osteosarcoma cells was at least partially realized through the inactivation of Wnt/β-catenin signaling pathway.
CONCLUSIONS: The combination of PPI and TRAIL is potentially a novel treatment strategy of osteosarcoma.

BACKGROUND: Beta-catenin-mutated hepatocellular adenomas (β-HCAs) can appear iso- to hyperintense at the hepatobiliary phase (HBP) at magnetic resonance imaging (MRI). Given the relatively lower prevalence of β-HCAs, prior studies had limited power to show statistically significant differences in the HBP signal intensity between different subtypes.
OBJECTIVE: To assess the diagnostic performance of HBP MRI to discriminate β-HCA from other subtypes.
METHODS: Systemic review and meta-analysis.
METHODS: Ten original studies were included, yielding 266 patients with 397 HCAs (9%, 36/397 β-HCAs and 91%, 361/397 non-β-HCAs).
UNASSIGNED: 1.5 T and 3.0 T, HBP.
RESULTS: PubMed, Web of Science, and Embase databases were searched from January 1, 2000, to August 31, 2023, for all articles reporting HBP signal intensity in patients with histopathologically proven HCA subtypes. QUADAS-2 was used to assess risk of bias and concerns regarding applicability.
METHODS: Univariate random-effects model was used to calculate pooled estimates. Heterogeneity estimates were assessed with I2 heterogeneity index. Meta-regression (mixed-effect model) was used to test for differences in the prevalence of HBP signal between HCA groups. The threshold for statistical significance was set at P < 0.05.
RESULTS: HBP iso- to hyperintensity was associated with β-HCAs (pooled prevalence was 72.3% in β-HCAs and 6.3% in non-β-HCAs). Pooled sensitivity and specificity were 72.3% (95% confidence interval 54.1-85.3) and 93.7% (93.8-97.7), respectively. Specificity had substantial heterogeneity with I2 of 83% due to one study, but not for sensitivity (I2  = 0). After excluding this study, pooled sensitivity and specificity were 77.4% (59.6-88.8) and 94.1% (88.9-96.9), with no substantial heterogeneity. One study had high risk of bias for patient selection and two studies were rated unclear for two domains.
CONCLUSIONS: Iso- to hyperintensity at HBP MRI may help to distinguish β-HCA subtype from other HCAs with high specificity. However, there was heterogeneity in the pooled estimates.
METHODS: 3 TECHNICAL EFFICACY: Stage 2.