Research Progress of LEF1 Gene in Malignant Tumors

Abstract

Currently, one of the most dynamic and rapidly advancing areas in biomedical research is the study of cell signaling systems. In particular, researchers have directed significant attention toward the Wnt signaling pathway, which has emerged as a critical player in several biological processes, including embryonic development, cancer progression, and the maintenance of tissue homeostasis. The growing body of research demonstrating the Wnt pathway’s critical functions in various activities emphasizes the pathway’s importance. Lymphoid enhancer factor-1 (LEF-1) is a crucial component of the Wnt signaling cascade, among its numerous components. The β-catenin/LEF complex, which is essential for triggering transcriptional responses, is formed when the N-terminal domain of LEF-1 binds with β-catenin. This complex acts as a central “activation hub” within the Wnt pathway, integrating signals from β-catenin and LEF-1 to facilitate gene expression that is critical for cellular functions. This narrative review focuses on highlighting the latest advancements in LEF-1 research, particularly its role in cancer. By emphasizing the significance of LEF-1 in the processes of carcinogenesis, the discussion aims to shed light on the potential implications of these findings for developing innovative treatment strategies. Understanding the function of LEF-1 not only enhances our comprehension of tumor biology but also opens pathways to novel therapeutic interventions.

Introduction

The TCF/LEF transcription factor family exhibits significant structural and functional diversity, generated through alternative splicing and context-specific promoter regulation. Among its key members, LEF-1 serves as a critical effector within the Wnt/β-catenin signaling pathway. Beyond its indispensable roles in embryonic stem cell specification and the maintenance of diverse adult tissues—including teeth, hair follicles, mammary glands, and airway submucosal glands—dysregulation of LEF-1 expression is increasingly implicated in pathological states. Notably, aberrant LEF-1 expression is a recurrent feature in numerous malignancies, underscoring its pivotal contribution to cancer initiation, progression, and metastasis. Clinical studies have demonstrated that the abnormal expression of LEF-1 is significantly associated with the poor prognosis of various malignant tumors. LEF-1 serves as both a valuable biomarker and a potential therapeutic target, highlighting its dual significance in clinical applications. This narrative review synthesizes current understanding of LEF-1’s complex functions in oncogenesis and provides a comprehensive overview of research efforts aimed at elucidating its mechanistic involvement in cancer pathogenesis.

LEF-1 Gene and Protein Structure

Gene structure of LEF-1

Nestled within the T cytokines (TCF)/LEF-1 cohort, LEF-1 is a member of the high mobility group (HMG) transcription factor family. ¹ Its primary method of operation is the complex manipulation of the DNA helix structure to control the expression of genes.^2,3 LEF-1, a prominent member of the multipromoter gene ensemble, frequently tells the story of aberrant and inconsistent activation in a variety of clinical environments. ⁴ LEF-1 has 2 isoforms with opposing functions: the full-length isoform promotes proliferation, ⁵ while the truncated isoform inhibits growth. ⁶ The full-length LEF-1 is currently the subject of scientific investigation. Being the primary mediator of the Wnt/β-Catenin signaling cascade, it skillfully takes charge of gene transcription and influences it both alone and in conjunction with β-catenin. ⁷ At present, there is a lack of direct clinical trial data for the treatment of cancer with full-length and short-length targeting of the LEF-1 subtype. However, combined with the progress in drug development of the WNT signaling pathway and the maturity of molecular typing technology, this strategy is expected to become a new direction for cancer treatment.

The latest genomic data for chromosome 4 have been released by the Human Genome Center at Stanford University. It focuses on the LEF-1 locus, which begins with intron 3 (GenBank entry numbers AC000016, AC21524). The gene itself spans at least 140 kb, and the mRNA open reading frame (ORF) is 1200 bp long. It is situated on chromosome 4 in the q23-g25 region. With a third intron that is 75 kb long and could include a selective exon, it has 12 exons and 11 introns. Hovanes et al ⁸ revealed in 2000 that full-length LEF-1 is the major promoter of LEF-1 and that it has a unique 1.2 k long and G-rich 5-untranslated region (5-UTR). This promoter is very active in the lymphocyte system and starts the transcription of a gene from a region that does not have a TATA core. The Sp1, E-box, beginning element, and LEF/TCF binding site are all included in the transcription starting region. ⁹ Hovanes et al found 2 different LEF-1 mRNA sizes, 3.6 and 2.2 kb, within normal thymus between 1991 and 2001.^3,10 They also discovered a secondary promoter in intron 2/exon 3, which results in an mRNA with a shortened 5-UTR that encodes a shortened version of LEF-1. A 110 bp Wnt/β-catenin response element (WRE) is present in the original LEF-1 promoter and is essential for controlling the production of mesenchymal cells and possible epithelium during the formation of fetal hair follicles. Furthermore, the first and second introns may control upstream promoters in addition to influencing cortical gland expression. ¹¹

A ribosome entry site (IRES) found in the mRNA 5-UTR of full-length LEF-1 was discovered by Jimenez et al and is thought to be involved in the translation process of full-length LEF-1. Meanwhile, their research identified a third LEF-1 promoter that produces a 3.0 kb mRNA. ⁶ These results highlight the LEF-1 gene’s intricate multipromoter properties and highlight the necessity for more research into its structural details.

LEF-1 protein domain

HMG DNA binding domain

Transcription factors that belong to the LEF/TCF family are identified by their shared structure of the High Mobility Group (HMG) box. These proteins have Gro/TLE binding domains, C-clamps, β-catenin binding domains, and DNA-binding domains. ¹² The High Mobility Group Box (HMGB) protein contains the HMG box, which has an L-shaped structure and normally has about 80 amino acids. ¹³ This structure is crucial for recognizing particular DNA structures or sequences since it is substantially conserved across many HMG boxes, despite the sequence homology being rather poor. ¹⁴ The proteins that are recognized by sequence-specific HMGB proteins include the sex-determining factor SRY, related Sox proteins, transcription factors such as LEF-1 and TCF-1, as well as fungal regulatory proteins like MatMc, Mat-a1, and Rox1.^15-17 However, certain DNA structures including supercoiled DNA, cross-shaped arrangements, and 4-way junctions are recognized by structure-specific HMGB proteins.^18-20 It is assumed that their natural role is to act as DNA chaperones, influencing DNA’s structure.

Understanding the relationship between DNA and the HMG DNA-binding domain has received more and more attention in recent years. The particular DNA binding of the chromosomal protein HMGB1 to the anti-tumor medication cisplatin cross-linking was initially described by Bruhn et al. ²¹ One important discovery by Chválová et al was the identification of double-stranded DNA motifs that may bend up to 9 base pairs in length by the HMG DNA-binding domain of LEF-1. This structural pattern resembles the geometric arrangement of 2 neighboring guanines (cisplatin GG), which are crosslinked by the anti-tumor medication cisplatin. Cisplatin-GG motifs can bind to LEF-1; however, they have a lesser affinity for LEF-1 than do 25 base pair oligonucleotides with 9 base pair motifs that can bind to LEF-1. Cisplatin-GG motifs can hijack transcription factors such as LEF-1 that include the HMG-Box. ²² The specific mechanism of this special domain needs to be further studied.

β-catenin binding domains

The binding domain of β-catenin is a crucial element that promotes the connection between β-catenin and members of the LEF/TCF family, which in turn has a substantial impact on the physiological and pathological actions of cells. Target genes are inhibited when β-catenin function is lost, and the Gro/TLE binding domain is involved in this process.^12,23 Thus, β-catenin determines whether LEF/TCF has an effect on downstream genes, and LEF/TCF is an essential bridge between downstream gene expression and β-catenin, and ultimately cell phenotype.

Variable C-end tail area

Another notable characteristic of all members of the LEF/TCFs family is the presence of multiple C-termini. The promoter of full-length LEF-1 is activated by β-catenin via 2 Wnt response elements; however, its activation is contingent upon β-catenin being recruited by a specific TCF isomer with an alternative C-terminal tail referred to as the “E-tail.” Certain subtypes of the LEF/TCF transcription factor family can selectively activate the LEF-1 promoter due to the presence of the E-tail. Thus, the shape of the E-tail influences the LEF/TCF transcription factor family’s activity. The E-tail’s residues are split into the highly conserved peptide motifs WCXXCRRKKKC and KKCRARFG. Every member of the TCF family shares these peptide motifs. ²⁴

Functional Research

After the first member of the Wnt family was discovered in 1982, the area of Wnt signaling has experienced a continuous surge in study. The drosophila wingless gene and the mouse breast cancer integrase-1 gene are the initial origins of the Wnt locus. Due to the similarity of functional proteins, researchers merged these 2 genes to form the Wnt gene. ²⁵ Within the Wnt signaling pathway exist both canonical and noncanonical pathways. The interaction of TCF/LEF and β-catenin is not necessary for noncanonical pathways such as the atypical Wnt planar cell polarity pathway and the Wnt/Ca²⁺ pathway. ²⁶ The canonical Wnt pathway, on the other hand, is connected to the activation of target genes through the nuclear translocation of β-catenin and the transcription factors TCF/LEF. The noncanonical route controls cell polarity and migration, while the conventional channel mainly controls cell proliferation. A reciprocal control network is created by combining these 2 main channels.^27-29 The nuclear, membrane, cytoplasmic, and extracellular signaling segments comprise the 4 components of the Wnt/β-catenin pathway.^30,31 Extracellular signals are transmitted through Wnt proteins such as Wnt3a, Wnt1, and Wnt5a. The membrane region features the Frizzled receptor, a specific 7-pass transmembrane protein, along with LRP5/6 coreceptors. ³² In the cytoplasm, key components include β-catenin, DVL, Glycogen Synthase Kinase-3β (GSK-3β), AXIN, APC, and casein kinase 1 (CK1). ³³ The nuclear section is mostly composed of the transcription factors TCF/LEF, downstream target genes such as c-Myc and MMPs, and β-catenin translocating into the nucleus. ³¹ The multiprotein destruction complex, comprising APC, Axin, CK1, and GSK-3β, is continuously cleaving the cellular β-catenin encoded by the CTNNB1 gene. When Wnt ligands bind to the LRP5/6 coreceptor and Frizzled receptor, they start the β-catenin-dependent Wnt pathway and stop the Disheveled protein from breaking down β-catenin. Consequently, β-catenin stabilizes and migrates to the nucleus, where it combines with TCF/LEF transcription factors to regulate the transcription of target genes, such as c-Myc and cyclin D1, thereby regulating cell proliferation ³⁴ (Figure 1). Adhesion, proliferation, differentiation, and migration are just a few of the cellular processes that the Wnt/β-catenin signaling system controls. It is crucial for embryonic development as well as the homeostasis of adult tissues, particularly the gut and breast gland. ³⁵ The role of LEF-1 in Wnt signaling has been extensively studied, as it is an essential part of the Wnt signaling pathway. Together with β-catenin, it forms a complex that affects cancer and development by inducing the transcription of target genes downstream.

Figure 1.

The classical Wnt signaling pathway involves a well-defined conduction mechanism. Wnt ligands initiate signal transduction by binding to Frizzled (Fz) receptors, a process that requires the coreceptor low-density lipoprotein receptor-related protein 5/6 (LRP5/LRP6) and the cysteine-rich domain (CRD) of the Fz receptor. Signal transduction can be categorized into 2 distinct states: the nonactivated state and the activated state. (A) Suppression state in the absence of Wnt signaling. In the absence of Wnt signaling, glycogen synthase kinase 3β (GSK3β) or related kinases mediate the phosphorylation of β-catenin, leading to ubiquitination and subsequent proteasomal degradation. Within the nucleus, members of the Groucho (Grg) family of inhibitors bind to the transcription factor Tcf-1, maintaining it in a transcriptionally inactive state and thereby suppressing the expression of Wnt target genes. (B) Signal transduction following Wnt activation . on binding to the Fz/LRP5/6 receptor complex, Wnt ligands activate the Disheveled (Dsh) protein, which inhibits GSK3β activity. This process involves the formation of a complex comprising the tumor suppressor Axin, adenomatous polyposis coli (APC), β-catenin, and GSK3β. on Wnt signal activation, β-catenin escapes GSK3β-mediated hyperphosphorylation and translocates into the nucleus. Within the nucleus, β-catenin directly interacts with the Tcf-1 transcription factor, initiating the transcriptional activation of target genes and thereby mediating the biological effects of Wnt signaling. Figure created by the authors using BioRender (https://www.biorender.com/).

Cancer

Malignant tumors are a major global health concern and the world’s primary cause of death. ³⁶ An aging population combined with a lack of good early detection techniques is expected to increase the global burden of human cancers. ³⁷ Cancer patient survival rates are still appallingly poor, despite advances in cancer management and treatment. ³⁸ Therefore, the search for novel and trustworthy biomarkers is vital in an effort to reduce the number of people dying from cancer. When β-catenin and LEF-1 are co-expressed in mammalian cells, they create a complex that is observable by immunoprecipitation and is located in the nucleus. ² The Wnt/β-catenin pathway is essential for several types of cancer tumorigenicity. The Wnt/β-catenin pathway’s downstream regulator, LEF-1, is essential for the upkeep of stem cells, the epithelial-mesenchymal transition (EMT), and tumor invasion.^39-42 Evidence, however, points to the possibility that LEF-1 has inhibitory effects as well. Lymphoid enhancer factor-1 has been shown by Dräger et al ⁴³ to suppress rhabdomyosarcoma growth, migration, and invasiveness both in vivo and in vitro. However, rhabdomyosarcoma is shown to overexpress LEF-1 in contrast to normal skeletal muscle. Therefore, this suggests that the dual role of LEF-1 as an oncogene or tumor suppressor is determined by the interaction of signaling pathways, tissue-specific environment, molecular interactions, etc. The role of LEF-1 in tumors is dynamically regulated by various mechanisms, including phosphorylation ⁴⁴ and m6A methylation, and is influenced by the activity of cofactors. ⁴⁵ These regulatory processes differ across tumor types, highlighting the diverse environment-dependent functions of LEF-1 in tumorigenesis. As a result, it is suggested that LEF-1 plays a variety of roles in the development and progression of tumors, calling for more research into the precise mechanisms behind its carcinogenesis and offering the possibility of developing into a novel therapeutic target. However, at present, the clinical treatment strategies for LEF-1 are still in the early stage and mainly rely on indirect intervention methods. Although inhibitors directly colon cancer have not yet been developed, significant progress has been made by interfering with the β-catenin/TCF4 interaction ⁴⁶ and regulating post-translational modifications. ⁴⁷

Colon cancers

The activation of the Wnt signaling pathway is a key factor in the development of numerous colorectal cancers. ⁴⁸ Due to the mutation of the CTNNB1 gene, which disrupts the degradation mechanism of β-catenin and consequently stabilizes it, this pathway becomes activated, leading to the accumulation of β-catenin in the cell nucleus. There, it interacts with transcription factors from the LEF-1 and TCF families (LEF/TCFs), including TCF1, TCF3, and TCF4, initiating the transcription of specific target genes. This process promotes the proliferation, metastasis, and drug resistance of colorectal cancer cells. ⁴⁹ While LEF-1 is typically not present in healthy adult colon tissue, its abnormal expression is observed in most cases of sporadic colorectal cancer, indicating that Wnt signaling plays a significant role in disease development. ⁸ LEF-1 generates 2.2 kb and 3.6 kb mRNA in normal thymic tissue,^3,10 however only the 3.6 kb mRNA is found in colon cancer and melanoma cells. ⁸ Development and homeostasis depend heavily on the Wnt pathway, and cancer is frequently linked to problems with this route.^50,51 Wnt pathway dysregulation is caused by mutations in APC and other components including β-catenin, Axin, or Ring Finger Protein 43 (RNF43) in most sporadic colorectal tumors.^52,53 APC promoter methylation-induced underexpression ⁵⁴ of Wnt ligands and Frizzled receptors, as well as overexpression of these proteins, are examples of deregulated expression of Wnt pathway components.^55,56 The significant role of dysregulated Wnt signaling in cancer is propelling the identification of effective treatment targets. Nevertheless, selecting appropriate therapeutic agents and targets poses a considerable challenge due to the intricate interactions among Wnt pathway ligands and receptors, along with the importance of key nodes in maintaining proper stem cell function and tissue homeostasis.

Pilomatricomas

Lymphoid enhancer factor-1 is generally linked to certain types of skin adnexal tumors, such as Pilomatricoma.^57-59 Researchers have suggested that the transition of hair stromal cells into the cortex during later developmental stages is influenced by the traditional Wnt signaling pathway. This idea arises from the functions of downstream effectors LEF-1 and β-catenin, which play a crucial role in activating cortical anterior hair keratin expression.^60,61 Supporting evidence includes the identification of LEF-1 binding sites within the proximal promoters of nearly all hair keratin genes.^62,63 The promoter for mHa1, which encodes cortical anterior keratin, can be activated in epidermal keratinocytes through interactions between LEF-1 and β-catenin. It is thought that differentiation into cortical cells initiates when both LEF-1 and β-catenin are co-expressed in nuclei located within hair follicles, resulting in the synthesis of hair keratin 1 (hHa1). ⁶¹ In contrast, cells that correctly express hHa1 but completely lack LEF-1 do not show a basal-like subset of hair keratins upon metastasizing to tumors, even though they exhibit nuclear co-expression of both LEF-1 and β-catenin. These observations indicate that pilomatricomas differ from normal hair follicles as they do not manage their cortical development through the conventional Wnt signaling pathway. This discovery strongly indicates that the role of LEF-1 (specifically, the function of the LEF-1/β-catenin complex) is highly environmentally dependent, even within tissues (hair follicles) of the same origin.

Breast cancer

In 2025, it is estimated that there will be 2 041 910 new cancer cases and 618 120 cancer deaths in the United States. Among malignant tumors affecting women, breast cancer accounts for 32% ⁶⁴ The illness known as breast cancer is diverse, with many biological subgroups that differ in terms of appearance, responsiveness to treatment, and clinical behavior. ⁶⁵ There have been reports of LEF-1 expression in breast cancer. ³⁵ Tumor invasion is aided by the epithelial-mesenchymal transition (EMT), which is brought on by overexpression of LEF-1. Therefore, it is reasonable to suggest that an increase in LEF-1 expression in cancer could result in the β-catenin binding partner transitioning from TCF4 to LEF-1, which may promote epithelial-mesenchymal transition (EMT) and enhance tumor invasion. ⁵⁰ Filali et al ⁶⁶ discovered in 2002 that the β-catenin/TCF4 complex has the ability to transcriptively activate LEF-1, indicating that LEF-1 functions as an amplifier of Wnt/β-catenin signaling. The mechanism of LEF-1 overexpression in breast cancer has only been little studied thus far; further investigation is needed.

Oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) accounts for over 90% of all oral malignancies and is a significant public health issue. ⁶⁷ In India and other South Asian countries, smoking, drinking alcohol and chewing betel nuts are among the main causes of cancer-related death.^68,69 The mutation of the GSK-3β phosphorylation site of β-catenin and the inactivation of APC also lead to the stability of β-catenin, resulting in the upregulation of TCF/ LEF-dependent transcriptional activity. ⁷⁰ This mutated β-catenin can act as an oncogene, and the mutation leads to the accumulation of the protein in the cytoplasm and/or nucleus of cancer cells. ⁷¹ The Wnt/β-catenin signaling pathway activates downstream targets through its interaction with TCF/LEF transcription factors, which subsequently promotes tumor growth, invasion, and metastasis. ⁷²

Prostate cancer

With 29% of all cases among men, prostate cancer is the second most common cause of cancer-related deaths in that demographic. ³⁶ Although androgen ablation treatment initially has a positive effect on prostate cancers, most tumors go from hormone-sensitive to hormone-refractory illness, known as castration-resistant prostate cancer (CRPC). ⁷³ Furthermore, extracellular elements that affect androgen receptor activation include Wnt proteins.^74,75 Wnt proteins are secreted proteins that are rich in cysteines and are essential for both adult tissue homeostasis and embryonic development. ²⁷ The stability of the transcriptional coactivator β-catenin, which is essential for the cadherin cell adhesion complex and controls the expression of several genes linked to cancer, is one of the hallmarks of the Wnt signaling pathway. ⁷⁶ β-catenin regulates the expression of various genes by interacting with members of the TCF/LEF-1 family. In addition, β-catenin binds to androgen receptors, which play a vital role in prostate growth and are key factors in the progression of prostate cancer. ⁷⁷ The Wnt/β-catenin pathway is thought to influence prostate cell proliferation, differentiation, and epithelial-mesenchymal transition while also affecting the invasive characteristics of tumor cellsl. ⁷⁸ Together with β-catenin, LEF-1, a crucial component of the Wnt signaling pathway, regulates these functions cooperatively.

Nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) is a kind of cancer that mostly affects people in southern China, Southeast Asia, and North Africa. Infection with the Epstein-Barr virus is linked to almost all occurrences of nonkeratinized nasopharyngeal cancer in South China. The principal histological types are as follows: keratinizing squamous cell carcinoma, nonkeratinizing carcinoma (differentiated and undifferentiated), and basaloid squamous cell carcinoma. The majority of patients have achieved disease control owing to the implementation of aggressive diagnostic strategies and targeted therapeutic interventions. However, a subset of cases still exhibits poor prognostic outcomes, primarily attributed to the occurrence of metastases. ⁷⁹ Wang et al ⁸⁰ showed that “nasopharyngeal cancer (NPC) was associated with aberrant activation of the β-catenin pathway, which includes β-catenin, cyclin D1, c-Myc, and MMP7. Individuals with overexpressed cyclin D1, c-Myc, MMP7, and aberrant β-catenin expression may have poor survival results.” No direct studies have incorporated LEF-1 into EBV-driven NPC tumorigenesis models, but cross-regulation at the molecular pathway level suggests a functional association. Furthermore, Zhang et al ⁸⁶ showed a noticeably greater positive expression rate of LEF-1 in their 2019 immunohistochemistry study of LEF-1 protein expression in nasopharyngeal cancer tissues. ⁸¹ LEF-1 expression also showed a strong correlation with lymph node metastasis (LNM), advanced clinical stage, and worse survival rates in individuals with nasopharyngeal cancer. Thus, there is enough data to conclude that individuals with nasopharyngeal cancer who have positive LEF-1 expression have a bad prognosis.

Glioblastoma

The most common malignant brain tumor in adults is glioblastoma (GBM), which is distinguished by a high degree of cellular heterogeneity and variable numbers of cancer cells. ⁸² The median survival of GBM patients is still fewer than 2 years, despite the disease’s daunting nature and the recent diversity and ongoing improvement of treatment approaches. ⁸³ Glioblastoma is characterized by the significant expression of LEF-1 and TCF1, with the sole expression of LEF-1 being able to distinguish glioblastoma from astrocytoma (II, III). ⁸¹ Malignant glioblastoma is characterized by elevated levels of TCF-1 and LEF-1, with LEF-1 potentially acting as a marker for malignant transition. ⁸¹

Hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a common malignant tumor with a high incidence and death rate worldwide. ⁸⁴ However, insufficient early identification has left advanced HCC patients with few effective treatment choices, meaning that most HCC patients have a poor prognosis.^85,86 Invasiveness is widely acknowledged as the primary driver of HCC metastasis and recurrence. ⁸⁷ An early indicator of HCC is overstimulating the Wnt/β-catenin signaling pathway.^88,89 About 50% of HCC patients had mutations in CTNNB1, AXIN1, or APC that activate the Wnt/β-catenin signaling pathway. ⁹⁰ LEF-1 plays a crucial role in the Wnt/β-catenin pathway. It interacts with the rising levels of β-catenin in the nucleus, leading to the transcription of Wnt target genes and promoting the growth of cancerous cells. ⁹¹

Solid pseudopapillary neoplasm

Solid pseudopapillary neoplasms (SPN) are exceedingly rare, comprising 0.3% to 2.7% of all exocrine pancreatic tumors. This tumor entity predominantly affects younger individuals and exhibits a pronounced female predilection. ⁹² Singh et al ⁹³ demonstrated that the LEF-1 protein was significantly overexpressed (nuclear positivity) in 93% of SPN cases (41/44), while its expression was minimal in other pancreatic tumors, such as ductal adenocarcinoma, neuroendocrine tumors, and acinar cell carcinoma (<5% positive cases). The overexpression of LEF-1 is directly associated with mutations in the CTNNB1, which result in abnormal stabilization of β-catenin. on nuclear translocation, β-catenin forms a transcriptional complex with LEF-1, thereby driving tumorigenesis. Geetha et al ⁹⁴ confirmed via IHC that LEF-1 exhibited consistent nuclear positivity in SPN (100%, 30/30 cases), with staining intensity correlating with tumor differentiation. Compared with other markers (eg, β-catenin and CD10), LEF-1 staining demonstrates clearer nuclear localization, reduced background interference, and superior diagnostic performance. It is therefore proposed that LEF-1 IHC should serve as the first-line diagnostic tool for SPN, particularly for small biopsy specimens or challenging cases. The aberrant expression of LEF-1 in SPN is attributed to dysregulation of the Wnt signaling pathway. Prospective studies conducted in 2024 have further validated its diagnostic value, which holds promise for reducing misdiagnosis rates and guiding precise treatment strategies.

Conclusion

Lymphoid enhancer factor-1, a member of the LEF-1/TCF family, is a nuclear effector of the Wnt/β-catenin signaling pathway. Its highly mobile group and highly conserved DNA-binding domain can be used to identify it. Lymphoid enhancer factor-1 is a transcriptional regulatory factor that controls the expression of several genes and influences the development of various malignant cancers. It has different functions in each kind of tumor (Table 1). Since little is presently known about how LEF-1 promotes tumor development, further research is needed to fully understand the role of LEF-1 in malignancies as well as related processes and pathways. The role of LEF-1 in cancer is intricately linked to complex molecular networks and dynamic regulatory mechanisms. Unraveling its unresolved mysteries necessitates the synergistic integration of multidisciplinary technologies. Cutting-edge advancements, including CRISPR, single-cell sequencing, and cryo-electron microscopy, have furnished unparalleled tools for elucidating LEF-1 function. Furthermore, the convergence of multiomics data and the utilization of organoid models have expedited the translation from mechanistic research to clinical applications. Future investigations should prioritize the noncanonical functions, isoform-specific regulation, and microenvironmental interactions of LEF-1, thereby establishing a robust foundation for the development of precision therapeutic strategies targeting LEF-1.

Table 1.

Summary of the LEF-1 alterations in malignant tumors.

Cancer type	LEF-1 expresses the trend	Key mechanisms/clinical associations
Colon cancers	High expression	Activate the Wnt pathway and promote metastasis48,49.
Pilomatricomas	Not clear	More research is needed for verification 60 .
Breast cancer	High expression	Promote EMT, enhance tumor invasiveness, and amplify signals 50 .
Oral squamous cell carcinoma (OSCC)	High expression	The CTNNB1 mutation activates the WNT signaling pathway70-72.
Prostate cancer	Controversy	β-catenin is associated with androgen receptors, and LEF-1 and beta-catenin work together to regulate the behavior of cancer cells77,78.
Nasopharyngeal carcinoma (NPC)	High expression	It works in synergy with Epstein-Barr virus infection and promotes proliferation80,81.
Glioblastoma (GBM)	High expression	Through the Wnt/β-catenin pathway, high expression may have a poor prognosis 81 .
Hepatocellular carcinoma (HCC)	High expression	Wnt pathway activation driver 91 .
Solid pseudopapillary neoplasm (SPN)	High expression	Mutations in the CTNNB1 gene lead to abnormal activation of the Wnt pathway, and LEF-1 is highly expressed as a downstream effector factor. Almost all SPN tumor cells showed strong nuclear positivity93,94.