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12 January 2025

Triple-Negative Breast Cancer Progression and Drug Resistance in the Context of Epithelial–Mesenchymal Transition

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Department of Biochemistry and Molecular Biology, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland
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These authors contributed equally to this work.
Cancers2025, 17(2), 228;https://doi.org/10.3390/cancers17020228
This article belongs to the Special Issue Triple Negative Breast Cancer Therapy Resistance and Metastasis
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Simple Summary

Triple-negative breast cancer (TNBC) is a challenging-to-treat breast cancer subtype, characterized by high recurrence, increased risk of metastasis, and lower survival for patients compared to other breast cancer subtypes. Depending on the clinical advancement of the disease, surgery, radiotherapy, and chemotherapy remain the standard treatment, though they often have limited long-term efficacy. Chemoresistance in TNBC is closely related to the epithelial–mesenchymal transition (EMT), a process where tumor cells gain mesenchymal-like characteristics. This, in turn, increases their metastatic potential and resistance to standard chemotherapeutic treatments. There is a growing interest in small-molecule inhibitors targeting EMT as a potential strategy to overcome resistance and improve TNBC patient outcomes. This review discusses the TNBC progression and drug resistance within the context of EMT, highlighting molecular features, key EMT protein markers, and signaling pathways. It also explores other mechanisms and factors related to chemoresistance in TNBC with an emphasis on treatment advancements.

Abstract

Triple-negative breast cancer (TNBC) is one of the most difficult subtypes of breast cancer to treat due to its distinct clinical and molecular characteristics. Patients with TNBC face a high recurrence rate, an increased risk of metastasis, and lower overall survival compared to other breast cancer subtypes. Despite advancements in targeted therapies, traditional chemotherapy (primarily using platinum compounds and taxanes) continues to be the standard treatment for TNBC, often with limited long-term efficacy. TNBC tumors are heterogeneous, displaying a diverse mutation profile and considerable chromosomal instability, which complicates therapeutic interventions. The development of chemoresistance in TNBC is frequently associated with the process of epithelial–mesenchymal transition (EMT), during which epithelial tumor cells acquire a mesenchymal-like phenotype. This shift enhances metastatic potential, while simultaneously reducing the effectiveness of standard chemotherapeutics. It has also been suggested that EMT plays a central role in the development of cancer stem cells. Hence, there is growing interest in exploring small-molecule inhibitors that target the EMT process as a future strategy for overcoming resistance and improving outcomes for patients with TNBC. This review focuses on the progression and drug resistance of TNBC with an emphasis on the role of EMT in these processes. We present TNBC-specific and EMT-related molecular features, key EMT protein markers, and various signaling pathways involved. We also discuss other important mechanisms and factors related to chemoresistance in TNBC within the context of EMT, highlighting treatment advancements to improve patients’ outcomes.

1. Introduction

According to Cancer Statistics, breast cancer (BC) is the most frequently diagnosed cancer, accounting for 32% of new cancer cases in 2024. Although significant progress has been made in the early detection and treatment of BC, it is still the primary cause of cancer-related mortality among females [1]. This clinically heterogeneous disease includes several distinct molecular subtypes, with the four most common being hormone receptor-positive (HR-positive) luminal A and luminal B, human epidermal growth factor receptor 2-positive (HER2-positive), and triple-negative breast cancer (TNBC). The luminal A subtype is defined as estrogen receptor (ER)/progesterone receptor (PR)-positive, HER2-negative, and Ki-67 protein expression index below 20%, reflecting the immunohistochemical staining outcomes for the patient samples. Ki-67 is a protein present in all active phases of the cell cycle but absent in the quiescent G0 phase. Hence, the level of Ki-67 expression reflects the proliferative activity of cancer cells and serves as the prognostic biomarker in BC [2]. High Ki-67 expression, defined as >30%, is associated with poorer prognosis in terms of disease-free survival (DFS) and overall survival (OS) of patients with TNBC [3]. High Ki-67 labeling index (LI) in the studied group of 52 TNBC patients was strongly associated with the presence of lymph node metastases, elevated tumor grade, advanced clinical stage, poor patient outcomes, and an inability to achieve pathological complete response (pCR) [4].
The luminal B subtype is ER/PR-positive (that may also lack the expression of PR), HER2-negative, and Ki-67 protein expression index ≥ 20%. HER2-positive subtype is characterized by HER2 overexpression but a lack of ER and PR receptors, while TNBC is marked by the absence of hormone receptors and HER2 expression (Figure 1A) [5,6]. Each molecular subtype of TNBC itself displays unique biological features [7,8,9] that contribute to its clinical behavior and therapeutic response. These subtypes are distinguished by specific molecular signatures, such as gene expression patterns, signaling pathway activation, and immune response regulation, which impact their aggressiveness, metastatic potential, and sensitivity to targeted treatments [9,10].
TNBC is a highly aggressive BC subtype, with its incidence steadily increasing. It is associated with the worst prognosis and a significantly shorter patient survival time compared to other BC subtypes [11,12]. Epidemiological and population-based studies indicate that TNBC primarily affects women under the age of 40 [13,14] and represents approximately 25% of all breast cancer cases [15]. The highest likelihood of TNBC recurrence occurs within the first three years, with a large number of deaths taking place within the first five years following the initial treatment [16]. The mortality rate for TNBC patients is approximately 40% within the first five years of diagnosis. The mortality rate within three months following TNBC recurrence can reach as high as 75%, reflecting the aggressive and treatment-resistant nature of the disease [17].
TNBC is characterized by a lack of effective treatment options. This is primarily due to the absence of ER, PR, and HER2 expression, which renders targeted and endocrine therapies ineffective. As a result, chemotherapy remains the primary therapeutic strategy for managing TNBC. In recent years, neoadjuvant chemotherapy (NACT) regimens, i.e., chemotherapy treatments administered before surgery, have become particularly important for treating TNBC [17]. These regimens aim to decrease the tumor size, making surgical removal of any remaining tumor tissue more feasible and less invasive [18]. It has been reported that TNBC patients achieve significantly higher rates of pCR with neoadjuvant chemotherapy compared to HR-positive BCs. This improved pCR is closely associated with better long-term outcomes, including reduced recurrence rates and enhanced survival [19]. Despite these, TNBC management faces challenges, especially related to treatment resistance. About half of the patients with localized TNBC who undergo NACT still have significant residual cancer burden (RCB-II or -III) as identified through the histopathological assessment of the breast tissue and axillary lymph nodes following surgery. This limited response to chemotherapy correlates with a 40–80% likelihood of disease recurrence, leading to distant metastasis and, for many patients, eventual death [20]. The introduction of immune checkpoint inhibitors (ICIs) made advancements in immunotherapy for TNBC. However, current evidence suggests that monotherapy with PD-1 (programmed cell death-1) or its ligand (PD-L1) inhibitors shows limited effectiveness, with only a small subset of patients experiencing substantial benefits [21]. These highlight an urgent need for deciphering molecular mechanisms related to TNBC progression and drug resistance to develop novel therapeutic approaches.
Epithelial–mesenchymal transition (EMT) is a process that promotes the detachment of cancer cells from the primary tumor, increasing their migratory and invasive potential, which makes them more likely to spread to surrounding tissues [22]. This transition contributes to TNBC’s aggressive nature and its resistance to conventional therapies [23], highlighting the importance of targeting EMT-related pathways for improving treatment strategies. The EMT process induced by signals from the tumor microenvironment (TME), such as growth factors, cytokines, and hypoxia, enables tumor cells to acquire mesenchymal characteristics. These changes include the loss of cell junction proteins, altered cell polarity, and enhanced stem cell properties, alongside cytoskeletal reorganization. As EMT progresses, overall mesenchymal markers (Figure 1B) such as vimentin and N-cadherin are upregulated, while the expression of epithelial markers such as E-cadherin decreases, leading to increased cancer cell motility and invasion (recently summarized by us in [24]).
Here, we discuss the current understanding of the TNBC progression and drug resistance within the context of the EMT process. Based on The Cancer Genome Atlas (TCGA) database (URL: https://www.cancer.gov/ccg/research/genome-sequencing/tcga (accessed on 16 November 2024)), we first analyze the frequency of the major somatic mutations in TNBC compared to other BC subtypes to briefly introduce the general, molecular landscape, as well as the expression levels of genes related to EMT in TNBC compared to other BC subtypes. We also present key EMT protein markers with an emphasis on TNBC progression. Moreover, we highlight the molecular mechanisms and signaling pathways associated with EMT in TNBC, particularly in relation to drug resistance and disease progression. Other mechanisms contributing to TNBC chemoresistance are also reviewed. A comprehensive understanding of molecular mechanisms and signaling pathways linked to the EMT process may help in the development of novel anti-cancer therapies for this highly aggressive and treatment-resistant BC subtype.
Cancers 17 00228 g001
Figure 1. The main characteristics of the triple-negative breast cancer (TNBC) subtype ((A); panel (A) adapted from [25] with modifications), and the schematic representation of the epithelial–mesenchymal transition (EMT) with the main EMT protein markers associated with TNBC (B). Created in https://BioRender.com.

2. Brief Overview of Molecular Landscape of Triple-Negative Breast Cancer (TNBC)

Lehmann et al. [26] proposed six distinct subtypes of TNBC based on gene expression profiling from 21 BC datasets and 587 TNBC patients’ samples. These are two basal-like subtypes (BL1 and BL2), luminal androgen receptor (LAR), immunomodulatory (IM), mesenchymal (M), and mesenchymal stem-like (MSL). BL1 is characterized by DNA repair and cell-cycle gene signatures, while BL2 shows enrichment in growth factor signaling and myoepithelial differentiation genes. The LAR subtype is linked to androgen receptor (AR) signaling. The IM subtype is linked to immune response regulation, and both M and MSL are enriched in genes associated with cell motility and EMT [27,28,29]. Burstein et al. [30]. categorized TNBC from 198 patients into four subtypes based on combined mRNA expression and DNA profiling, namely: luminal/androgen receptor (LAR), mesenchymal (MES), basal-like immunosuppressed (BLIS), and basal-like immune activated (BLIA), each with distinct molecular features related to immune regulation and DNA damage response pathways. More recently, transcriptomics data also provided classification into four subtypes based on the cohort of 465 primary TNBCs, i.e., basal-like immune-suppressed, luminal androgen receptor (LAR), immunomodulatory, and mesenchymal-like [10]. Noteworthy, quadruple-negative breast cancer (QNBC) was also distinguished, and it lacks the expression of four receptors such as ER, PR, HER2, and AR. However, this category is not established as a clinical category, and it is not used in clinical practice [31,32].
TNBC is the most commonly observed subtype in patients with BRCA1 germline mutations [33]. Over 85% of BCs arising in individuals with BRCA1 pathogenic variants exhibit a triple-negative phenotype. Additionally, about 11% to 19% of patients diagnosed with TNBC have either germline or somatic BRCA1 mutations, highlighting the genetic link between BRCA1 alterations and this aggressive breast cancer subtype [34,35]. One of the most prevalent somatic mutations in TNBC are mutations in the TP53 gene (~80%), which encodes the p53 protein (Figure 2). The p53 protein plays an important role in maintaining homeostasis and genome integrity by regulating cell cycle arrest, DNA repair, and apoptosis [36,37]. Similar to our representation of somatic mutation prevalence from the TCGA database, previous research has shown that mutations in the TP53 gene occur in over 65–80% of TNBC cases [38,39]. Below, we present recent data on the mutational landscape of TNBC with ten selected genes with the highest mutation frequency (somatic mutations) generated from the TCGA-BRCA database. Notably, TP53 shows a significantly higher mutation frequency in TNBC (80%) compared to other breast cancer (BC) subtypes (23%), while PIK3CA exhibits a lower mutation frequency in TNBC (15%) compared to nTNBC (40.3%). The genetic landscape underlying TNBC is linked to various hallmarks of tumor biology, cell invasion, drug resistance, and immune evasion.
Figure 2. The frequency of somatic mutations in triple-negative breast cancer (TNBC; red) versus other breast cancer subtypes (nTNBC; teal) based on data from The Cancer Genome Atlas (TCGA) database (URL: https://www.cancer.gov/ccg/research/genome-sequencing/tcga (accessed on 16 November 2024)) using TCGAbiolinks package. Mutation data for breast cancer subtypes were processed with the maftools package, and the mutation dataset originates from the study [40] (URL: https://doi.org/10.1016/j.cels.2018.03.002 (accessed on 16 November 2024)). The most frequently mutated genes are shown along with their mutation rates in TNBC samples. The x-axis represents the different mutated genes, while the y-axis indicates the percentage of samples exhibiting mutations in each gene. TP53 exhibits the highest mutation frequency (80%) in TNBC, whereas PIK3CA shows a notably lower mutation rate compared to other breast cancer subtypes (15%). Data represent ten selected genes with the highest mutation frequency. TP53—Tumor Protein P53, TTN—Titin, MUC16—Mucin 16, PIK3CA—Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha, USH2A—Usher Syndrome Type 2A, SYNE1—Spectrin Repeat Containing Nuclear Envelope Protein 1, FAT3—FAT Atypical Cadherin 3, FLG—Filaggrin, PKHD1L1—Polycystic Kidney and Hepatic disease 1 like 1, SPTA1—Spectrin Alpha Chain, Erythrocytic 1.

3. The Role of Epithelial–Mesenchymal Transition (EMT) in TNBC

3.1. The EMT Process Overview

The EMT is a well-conserved, multi-step, reversible process that plays roles in both physiological and pathological contexts, including embryonic development, wound repair, tissue fibrosis, or cancer progression [24,41,42,43]. Complex molecular mechanisms and signaling pathways involved in the EMT are stimulated by the signals from the local microenvironment, such as cytokines, growth factors, hypoxic conditions, and components of the extracellular matrix, initiating the process [44]. The EMT is also driven by the activation of specific transcription factors (TFs) that modify gene expression, resulting in reduced cell–cell adhesion. Cells lose intercellular adhesion and apico-basal polarity with a transition to anterior–posterior axial polarity. These alter the cytoskeletal structure and transition their phenotype from an epithelial to a mesenchymal, affecting both their form and function. Cells simultaneously acquire stem-cell-like traits and migratory and invasive characteristics [45,46]. Dysregulation of EMT is a key factor contributing to cancer-related mortality. It plays a crucial role in metastasis and the development of treatment resistance [47,48].
As aforementioned, EMT is regulated by a number of TFs, such as Snail, Slug, Twist, and ZEB1/2, that inhibit the expression of genes responsible for epithelial properties, while activating genes associated with the mesenchymal phenotype [49]. Moreover, the process is regulated by epigenetic and post-translational modifications (PTMs), including DNA methylation, chromatin remodeling, acetylation of histones and phosphorylation, as well as modifications of non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) [50,51]. Both internal and external factors that influence EMT are presented in Table 1, with internal being intrinsic to the cell and external involving signals and environmental conditions outside the cell.
Table 1. Key factors that influence epithelial–mesenchymal transition (EMT) and their impact on TNBC.
The reverse process, termed mesenchymal–epithelial transition (MET), involves mesenchymal cells reorganizing their cytoskeleton, restoring apical–basal polarity, and increasing their intercellular adhesion. These changes lead to the formation of an organized epithelial structure [71]. MET facilitates metastatic colonization by enabling cancer cells to re-acquire epithelial traits, such as cell adhesion and proliferation, which are diminished during EMT. While EMT enhances motility, it often suppresses proliferation, requiring tumor cells to alternate between migratory and proliferative states for efficient metastasis. For instance, suppressing Twist1 at secondary sites promotes proliferation and metastatic growth. However, colonization, the rate-limiting step of metastasis, depends on additional molecular events beyond EMT reversal [72]. The underlying mechanisms behind these processes remain incompletely understood. During cancer progression, epithelial-originating cancer cells undergo a process called partial EMT, where they display a combination of mesenchymal and epithelial characteristics, resulting in a hybrid E/M phenotype. This partial EMT is believed to increase the invasiveness of cancer cells, contribute to the formation of circulating tumor cells (CTCs; the cells that have dissociated from the primary tumor, entered the bloodstream, and can migrate throughout the body) and cancer stem cells (CSCs), and foster resistance to anti-cancer therapies [73]. Interestingly, CTCs from BC patients showed significant enrichment of mesenchymal markers compared to primary tumor cells, supporting the role of EMT in metastasis. Serial CTC monitoring revealed that mesenchymal CTCs were associated with disease progression, with dynamic shifts in cell fates observed during therapy cycles. These findings highlight the involvement of EMT regulators, e.g., TGF-β (transforming growth factor-beta), in the spread of BC [74].

3.2. EMT Protein Markers in TNBC and Their Role in Tumor Progression

The EMT process in TNBC involves the expression of specific protein markers that define and regulate the shift from an epithelial to a mesenchymal phenotype. These markers are categorized into epithelial markers, such as E-cadherin, cytokeratins, zonula occludens-1, claudin, occludin, and mesenchymal markers, including N-cadherin, vimentin, and fibronectin, alongside other EMT-related proteins like MMPs (matrix metalloproteinases). The process of EMT involves cytoskeletal reorganization, the loss of epithelial features, such as apical–basal polarity and strong cell–cell adhesion, coupled with the acquisition of mesenchymal traits, including front–back polarity and invasive morphology, the loss of expression of adhesion proteins such as E-cadherin, and increased expression of mesenchymal markers such as N-cadherin, vimentin and fibronectin [75].
Some of the proteins, however, cannot be classified as strictly epithelial or mesenchymal markers, as their roles and expression patterns are highly context-dependent. For instance, integrins, belonging to the family of transmembrane receptors that mediate cell adhesion to the ECM [76], may be associated either with epithelial or mesenchymal phenotype. Integrin α6β4 is often associated with epithelial cells, where it is predominantly expressed. Its expression tends to decrease as cells lose their epithelial characteristics [77]. It also shows a high expression level in TNBC, where it plays a significant role in tumor progression and drug resistance [78]. On the other hand, integrins like, e.g., α5β1, αvβ6, and αvβ3 are more commonly upregulated in mesenchymal cells. These integrins interact with components of the ECM, such as fibronectin and vitronectin, promoting migration, invasion, and survival, hallmarks of mesenchymal phenotypes during EMT [79]. Other proteins important in the context of TNBC progression, migration, invasion, and treatment resistance that are also linked to the EMT process are integrin α7 protein encoded by the ITGA7 gene and semaphorin 6 D encoded by the SEMA6D gene [80,81].
To evaluate the expression of genes encoding some of the protein markers involved in EMT in TNBC, as well as other EMT-related genes, we generated a heatmap that represents the gene expression profiles across three phenotypic groups: TNBC, other breast cancer subtypes (nTNBC), and normal tissues (Figure 3). Distinct expression patterns that differentiate TNBC from nTNBC were assessed. Gene expression data were derived from the TCGA-BRCA dataset, based on RNA-seq analysis, with samples grouped according to their phenotypic classification. Expression levels for each gene were normalized, log-transformed, and standardized to ensure comparability across samples. The threshold was set as |log2(expression)| ≥ log2(1.5), and statistical significance was considered as adjusted p-value < 0.05. The heatmap was constructed using hierarchical clustering of samples, enabling the identification of expression patterns and clustering trends that distinguish TNBC from other breast cancer subtypes.
Figure 3. A heatmap representing the gene expression profiles of EMT-related genes across TNBC, other breast cancer subtypes (nTNBC), and normal tissues. The data were derived from the TCGA database, with expression levels normalized, log-transformed, and standardized for comparability. The analysis incorporates mutation data from the Broad Institute TCGA Genome Data Analysis Center (2016), generated using MutSig 2CV v3.1 [82]. Genes with an expression threshold of |log2(expression)| ≥ log2(1.5) and statistical significance adjusted p-value < 0.05 were included (significant—orange and not significant—gray). Hierarchical clustering was performed for samples, revealing distinct expression patterns that differentiate TNBC from nTNBC. Expression levels above the median are shown in red (upregulated), those below the median in blue (downregulated), and values close to the median in white. Color intensity reflects the magnitude of deviation from the median. FOXC2—Forkhead Box C2, KRT18—Keratin 18, KRT8—Keratin 8, MMP9—Matrix Metallopeptidase 9, NOTCH1—Notch Receptor 1, SNAI1—Snail Family Transcriptional Repressor 1, ZEB1—Zinc Finger E-box Binding Homeobox 1, VIM—Vimentin, TCF3—Transcription Factor 3, CDH2—Cadherin 2, MMP2—Matrix Metallopeptidase 2, CDH1—Cadherin 1, FN1—Fibronectin 1, ACTA2—Actin Alpha Cardiac Muscle 2, SNAI2—Snail Family Transcriptional Repressor 2, PIK3CA—Phosphatidylinositol 4,5-bisphosphate 3-kinase Catalytic Subunit Alpha, TGFB1—Transforming Growth Factor Beta 1, CTNNB1—Catenin Beta 1, PTK2—Protein Tyrosine Kinase 2, ITGB1—Integrin Subunit Beta 1, TWIST1—Twist Family BHLH Transcription Factor 1, ITGA5—Integrin Subunit Alpha 5, ZEB2—Zinc Finger E-box Binding Homeobox 2.
This analysis revealed a significant upregulation of genes associated with EMT in TNBC compared to nTNBC. Specifically, increased expression was observed for EMT transcription factors (e.g., SNAIL1, ZEB1), transcriptional regulators (e.g., FOXC2, NOTCH1), and EMT markers (e.g., VIM, KRT18, KRT8) as well as MMP9. Hierarchical clustering and heatmap analysis highlighted these distinct molecular profiles separating TNBC from other BC subtypes (nTNBC) in the context of EMT-related genes.

3.2.1. The Main Epithelial Markers and Their Involvement in TNBC Progression

There are several proteins associated with epithelial cell phenotypes that are frequently used to characterize the epithelial features of cancer cells and also play an important role in TNBC progression. Among the most common epithelial markers that exhibit decreased expression in TNBC are E-cadherin, β-catenin, and cytokeratins. Additionally, proteins integral to tight junctions (TJs), such as claudins and occludin, as well as scaffolding proteins like ZO-1 (zonula occludens-1), are linked to the epithelial state and often show reduced expression in TNBC, reflecting a loss of epithelial characteristics during disease progression. The major epithelial markers and proteins associated with EMT that are involved in TNBC progression are described below.
E-Cadherin
E-cadherin, encoded by the CDH1 gene, is a key adhesion protein that plays a role in maintaining epithelial integrity by forming adherens junctions, which are essential for tight intercellular adhesion. Under physiological conditions, E-cadherin acts as a suppressor of tumor invasion [83,84]. As aforementioned, the process of EMT plays a pivotal role in tumor cell invasion and metastasis, enabling cancer cells to transition from an epithelial to a mesenchymal phenotype, thus enhancing their motility and capacity to overcome tissue barriers. E-cadherin loss or reduced expression is one of the key markers of EMT, observed in approximately 67% of TNBC patients [85]. The reduction or entire loss of E-cadherin in TNBC facilitates tumor progression by promoting the EMT process [86]. Tang et al. [85] have shown that the loss of E-cadherin is significantly correlated with poorer clinical outcomes for TNBC patients, including shorter DFS and OS. TNBC patients with reduced E-cadherin expression exhibited significantly shorter DFS (p = 0.016) and OS (p = 0.012) compared to those with higher E-cadherin expression. This loss of E-cadherin expression is also associated with poor prognostic features, such as, for instance, tumor size and lymph node status, further highlighting the role of E-cadherin in TNBC progression [85]. Kashiwagi et al. [87] observed that among a cohort of 574 primary breast cancer patients, reduced E-cadherin expression was more frequent in TNBC and correlated with worse patients’ outcomes, particularly in clinical stage II of the disease. Multivariate analysis confirmed reduced E-cadherin expression as an independent prognostic factor, suggesting its potential as a marker for defining TNBC subgroups and guiding treatment decisions [87]. A study by Jeong et al. [88] found that EMT characteristics were particularly prominent in TNBC compared to HR-positive breast cancer. These features were significantly associated with high histological grade (p-value < 0.001) as assessed by immunohistochemistry (IHC). The study also observed a decreased expression of E-cadherin in 16.7% of TNBC patients, indicating a loss of epithelial markers associated with the transition to a mesenchymal phenotype in TNBC. The presence of mesenchymal markers, such as vimentin (24.5% of patients) and N-cadherin (13.7% of patients) [88] suggests that EMT plays a crucial role in the aggressive nature of this tumor subtype, potentially contributing to poorer prognosis and increased metastatic potential.
β-Catenin
β-catenin serves two main roles. First, it is an essential part of E-cadherin and other cadherin-based cell adhesion complexes, which are important for maintaining the structural integrity and functional organization of epithelial cells and tissues. Second, β-catenin acts as a primary mediator in the canonical Wnt (Wingless/Integrated) signaling pathway. When this pathway is activated, β-catenin accumulates in the cytoplasm and subsequently translocates to the nucleus, where it interacts with T-cell factor (TCF)/lymphoid enhancer factor (LEF) transcription factors to regulate the expression of Wnt target genes [89,90]. In this way, β-catenin is central to both cadherin-mediated cell adhesion and the Wnt signaling. It has been shown that loss of cadherin-mediated adhesion promotes β-catenin release, leading to increased signaling activity, a process facilitated by proteases, protein kinases, and other molecular factors. Moreover, the Wnt signaling pathway is interconnected with cadherin adhesion as it targets related genes, including transcription factor-encoding genes (e.g, TWIST1, SLUG1), genes encoding metalloproteases and/or the cell adhesion molecule L1; both of the latter promote E-cadherin degradation. These interconnections provide a mechanism by which the loss of cadherin and enhanced Wnt signaling drive EMT, contributing to both TNBC development and progression [91]. In TNBC, a frequently activated Wnt signaling pathway contributes to the aggressive nature and poor prognosis of this subtype, regulating key tumorigenic behaviors, such as cell migration, stemness, anchorage-independent growth, and chemoresistance. Given its central role in TNBC progression, targeting β-catenin offers potential therapeutic value in managing this challenging cancer subtype [92]. In a study of 72 TNBC cases, reduced membranous expression of E-cadherin and β-catenin was observed in 56% of tumors, with a strong correlation between these two markers. The reduced expression level of both was significantly associated with poor OS and disease-specific survival (DSS), and multivariate analysis confirmed that β-catenin expression was an independent prognostic factor. These findings highlight the important role of E-cadherin and β-catenin as prognostic markers in TNBC, independent of conventional clinicopathologic factors [93]. Buechel et al. [94] investigated the distinct roles of β-catenin’s cell adhesion and transcriptional functions in metastatic breast cancer using the mouse mammary tumor virus–polyoma middle T antigen (MMTV-PyMT) model. They found that both functions are crucial for tumor cell survival, with β-catenin’s transcriptional activity being essential for EMT and metastasis. The loss of β-catenin’s transcriptional activity resulted in reduced primary tumor growth, invasion, and metastasis, underlining its critical role in cancer progression. This study highlights the importance of β-catenin’s transcriptional function in driving malignant BC progression [94].
Cytokeratins
Cytokeratins (CKs), as key components of the cytoskeleton in epithelial cells, serve as markers of epithelial differentiation, particularly in the context of TNBC [95,96]. CKs such as CK5/6, CK14, and CK8/18 are markers of basal-like and luminal epithelial differentiation [97,98], and their expression patterns reflect the heterogeneity of the TNBC subtype. It has been shown that the expression of CK5/6 and CK14 in TNBC correlates with increased tumor aggressiveness and poorer patients’ survival and prognosis [95,99,100]. In a recent study examining EMT in breast cancer subtypes across different species, human TNBC showed decreased expression of CK8/18 and increased expression of CK5/6 and CK14 as assessed by IHC on eleven specimens. These changes contribute to the enhanced migratory and invasive capabilities of TNBC cells, thereby promoting disease progression and metastasis [101]. However, larger cohorts should be analyzed using IHC or complementary methodologies to validate the expression levels of these proteins, their clinical significance, and implications. CKs may potentially also serve as therapeutic targets in TNBC.
Claudins
Claudins (CLDNs) are essential cell adhesion molecules that form TJs, regulate paracellular permeability, and maintain cell polarity [102,103]. Disruption of TJs can trigger EMT, which leads to the loss of cell–cell contacts, including the loss of E-cadherin, facilitating tumor invasion and metastasis [42,104,105]. Genomic studies have uncovered a claudin-low subtype of triple-negative breast cancer (TNBC), characterized by reduced expression of CLDN3 (claudin 3), CLDN4 (claudin 4), CLDN7 (claudin 7), and E-cadherin [106,107]. More recently, Geoffroy et al. [108] have shown that the loss of CLDN1 (claudin 1) correlates with increased invasiveness and higher recurrence of TNBC. Overall, the expression of CLDN1 is absent or strongly diminished in 76% of TNBC cases [109]. Transient overexpression of CLDN1 in MDA-MB-231 and Hs578T TNBC cell lines (which typically also have low CLDN1 expression), reduced cell migration, as demonstrated by wound healing and transwell assays. Stable overexpression of CLDN1 in MDA-MB-231 clones correlated with reduced cell migration, enhanced cell–cell aggregation, and the formation of β-catenin adherens junctions and occludin TJs. CLDN1 was also identified as a key factor in inhibiting cell migration, linked to the loss of stress fibers [108]. In patients with TNBC, altered expression of CLDNs has been associated with aggressive disease characteristics and poor patients’ prognosis. Specifically, high expression levels of CLDN1, CLDN4, and CLDN7 in TNBCs were more frequently observed compared to other BC subtypes, correlating with increased proliferative activity as indicated by the Ki67 labeling index. Notably, the combination of high CLDN4 and low CLDN7 expression was found to be an independent predictor of axillary nodal metastasis. Furthermore, low expression of CLDN1 and CLDN7, along with the loss of E-cadherin, was associated with poor recurrence-free survival (RFS), highlighting their potential as prognostic markers in TNBC [110]. These findings emphasize the involvement of claudins in EMT, metastasis, and overall tumor aggressiveness in patients with TNBC.

3.2.2. The Main Mesenchymal Markers in TNBC

Induction of EMT in TNBC leads to an increase in the expression of mesenchymal markers, including vimentin, N-cadherin, fibronectin, and other proteins related to mesenchymal states such as Fsp1 (fibroblasts specific protein 1) or MMPs (matrix metalloproteinases) that are activated along with pro-migratory signaling [111].
Vimentin
In the physiological context, vimentin (VIM) plays a significant role in several cellular functions, including maintaining cell shape and anchoring organelles. It is a key regulator of the cytoskeleton, supporting not only dynamic changes in cell shape but also enabling cell migration and invasion. By reorganizing the cytoskeleton, vimentin also facilitates the detachment of cancer cells from the primary tumor and their penetration into surrounding tissues. Moreover, it aids in the reorganization of actin filaments, further enhancing the motility of cancer cells [112,113,114].
Vimentin, as a mesenchymal marker in TNBC, is highly expressed in this BC subtype compared with other subtypes [115] and correlates with cancer invasiveness. Vimentin expression in TNBC is regulated by EMT-associated transcription factors, e.g., Snail1 and Twist1, which downregulate epithelial markers like E-cadherin, while promoting the expression of mesenchymal markers like vimentin or N-cadherin [49,116]. Ki-67 LI expression in TNBC cases is also significantly correlated with vimentin expression, highlighting its association with the EMT process [4]. TNBC cells (MDA-MB-231, SUM159-PT cell lines) with high vimentin expression exhibit enhanced migratory and invasive capabilities as observed in vitro and in a zebrafish model. This contributes to increased aggressiveness, which is associated with chemotherapeutic treatment-induced changes, where vimentin contributes to increased sphere formation and AKT phosphorylation [117]. These findings highlight vimentin as an important player in promoting invasion and potential drug resistance in TNBC, pointing to its potential as a therapeutic target in combating TNBC aggressiveness and recurrence. IHC-based studies conducted by Jeong et al. [88] revealed that approximately 24.5% of TNBC patients show high vimentin expression, compared to only 4.1% in receptor-positive cancers. This also strongly suggests that vimentin is closely associated with more aggressive forms of breast cancer.
Recently, Grasset et al. [118] showed that TNBC often displays EMT markers, though highlighting that the role of EMT in TNBC metastasis remains unclear. Through genetically engineered mouse models (GEMMs), patient-derived xenografts (PDXs), and patient samples, they identified large populations of hybrid epithelial/mesenchymal (E/M) cells leading to cancer invasion. The mesenchymal marker vimentin was found to enhance this invasion but limit metastatic growth. TNBC employs a vimentin-driven hybrid EMT, facilitating the formation of metastases with a mix of epithelial and mesenchymal traits. The decrease in vimentin expression level significantly decreased invasion capacity in the 3D culture models (both GEMM and PDX). EMT TFs showed distinct roles in invasion versus colony formation, with single-cell RNA sequencing (scRNA-seq) analysis revealing three EMT-related patterns. Notably, TNBC cells shifted from epithelial to hybrid E/M and mesenchymal patterns during invasion, and largely from epithelial to hybrid E/M state during colony formation. Both GEMM and patient samples displayed significant variability within and between metastases, suggesting multiple molecular strategies for organ colonization [118]. These results highlight the complex role of EMT in TNBC metastasis.
N-Cadherin
N-cadherin, encoded by the CDH2 gene, is a calcium-dependent adhesion molecule, characteristic of mesenchymal cells. During EMT, the downregulation of E-cadherin expression contributes to the loss of adhesive properties in epithelial cells and the acquisition of mesenchymal traits, marked by the upregulation of N-cadherin. This so-called “cadherin switch” is considered a hallmark of EMT, also significantly enhancing the migratory potential and cancer invasiveness and deteriorating patients’ outcomes [75,119,120]. The expression of N-cadherin is regulated by several EMT-associated transcription factors, such as Snail, Slug, and Twist, which repress epithelial markers while activating mesenchymal markers [66,121]. Immunohistochemical analyses revealed that N-cadherin is expressed in approximately 13.7% of TNBC patients, compared to only 5.9% in hormone HR-positive breast cancers. This increased expression in TNBC correlates with a higher histological grade and a more aggressive disease phenotype. Furthermore, N-cadherin expression is associated with shorter DFS and OS [88]. N-cadherin has also been shown to significantly impact prognosis, as its expression is linked to poorer outcomes in various cancer types. In line with this, Aleskandarany et al. [122] further emphasized the role of N-cadherin as a marker of aggressive disease, strengthening its potential as a prognostic factor in TNBC. Furthermore, N-cadherin facilitates the interaction between cancer cells and the stromal environment, particularly with cancer-associated fibroblasts (CAFs), by mediating a heterophilic adhesion that promotes invasion. High N-cadherin expression also enhances the mechanical activity of this interaction, supporting cancer cell invasion and repolarization of CAFs, which is crucial for the progression of cancer and potential metastasis [123]. These findings highlight the importance of N-cadherin in tumor progression, as its role in regulating stromal interactions contributes to both cancer cell spread and the dynamic reorganization of the TME. The expression of N-cadherin is also associated with plasticity and hybrid epithelial/mesenchymal (E/M) phenotypes in TNBC cells. These phenotypes increase cell plasticity, enabling adaptation to variable microenvironmental conditions during metastasis and contributing to therapeutic resistance [118,124].
Targeting N-cadherin or its regulatory pathways could provide a therapeutic strategy for TNBC. Blocking N-cadherin-mediated intercellular interactions through peptides or small molecules could offer a novel approach to treating this cancer subtype [125]. Early investigations into N-cadherin antagonists, such as ADH-1 (adherex 1), have demonstrated their potential as anti-cancer agents, with promising results in clinical trials for melanoma [126] and indications of efficacy in ovarian cancer [127]. In contrast, our earlier studies demonstrated that histone deacetylase inhibitors (HDIs), such as valproic acid and vorinostat, inhibit the proliferation and migratory activity of TNBC cell lines, while unexpectedly increasing the expression of N-cadherin in these cells. We hypothesized that cancer cells might adapt to HDIs’ treatment by upregulating structural proteins like N-cadherin to enhance their survival. Alternatively, the epigenetic mechanisms of HDIs might influence cadherin gene expression as “a side effect” of their effects on chromatin structure and activity. This phenomenon is of clinical interest, as understanding the phenotypic changes in tumor cells could be crucial for optimizing patients’ therapy [128]. Further research is necessary to explore the full therapeutic potential of these antagonists, small-molecule or histone deacetylase inhibitors, and monoclonal antibodies targeting N-cadherin in the EMT process and associated pathways in TNBC.

5. Discussion

TNBC is characterized by the lack of expression of ER, PR, and HER2 receptors. In contrast to non-TNBC subtypes, TNBC is often associated with a more aggressive clinical course, worse patient outcomes, and minimal responsiveness to hormonal therapies [242]. EMT plays a critical role in driving the aggressive nature of this BC subtype by promoting tumor cell plasticity, immune evasion, and metastatic potential [118,243]. This aggressiveness is further exemplified by the high mutation frequency of TP53 (~80%) in TNBC, which is consistent with prior studies reporting mutations in 65–80% of cases [38,39]. TP53 mutations impair the tumor-suppressive functions of the p53 protein, affecting key processes such as cell cycle regulation, DNA repair, and apoptosis, ultimately contributing to TNBC’s poor prognosis. Additionally, our findings of a lower mutation frequency in PIK3CA (15%) in TNBC, compared to its higher frequency in other BC subtypes (40.3%), suggest that distinct molecular mechanisms drive TNBC. Recent findings by Zaikova et al. [244] highlight the utility of circulating tumor DNA (ctDNA) as a biomarker for detecting drug resistance in TNBC. In this study, ctDNA detection within seven months of completing primary treatment identified residual disease in 7.7% of patients. Notably, incomplete pathological response combined with positive ctDNA was associated with significantly reduced DFS in patients treated with neoadjuvant therapy [244]. These results suggest that integrating such ctDNA analysis could aid earlier identification of drug resistance in TNBC.
Based on our recent results from the TCGA database (Figure 3), we observed significant upregulation of genes encoding key EMT transcription factors, including SNAIL1 and ZEB1, the EMT-related transcriptional regulators such as FOXC2 and NOTCH1, as well as genes encoding EMT marker proteins VIM, KRT18, KRT8 as well as MMP9, in TNBC compared to other breast cancer subtypes (nTNBC). Among these, transcription factors and regulators of transcription drive the EMT process by repressing epithelial markers and promoting mesenchymal gene expression [179,245,246]. The EMT marker proteins, such as VIM, KRT18, KRT8, and MMP9 are involved in cell structure, motility, and matrix remodeling, which are crucial for tumor invasion and metastasis [247]. The heatmap analysis, along with hierarchical clustering, revealed distinct molecular profiles that to some extent differentiate TNBC from nTNBC. The observed upregulation of transcription factors encoding genes (e.g., SNAIL1 and ZEB1) and transcriptional regulators (e.g., FOXC2 and NOTCH1) indicates that TNBC tumors are more likely to undergo EMT, while generally the activated mesenchymal marker genes are associated with a shift to a more invasive phenotype. For instance, the upregulation of VIM signifies a mesenchymal transition, which is associated with enhanced cell motility, invasiveness, and metastasis [118,248]. The dysregulation of cytokeratins KRT18 and KRT8 in TNBC may suggest that TNBC cells retain a hybrid epithelial–mesenchymal state rather than undergoing complete EMT, enabling them to balance structural stability and invasiveness, which is crucial for metastasis. Moreover, MMP9 is important for degrading extracellular matrix components, facilitating tumor invasion and metastasis [249,250].
The findings presented in this review highlight the critical role of the EMT process in TNBC progression and suggest that targeting both EMT transcription factors and markers could offer promising therapeutic strategies to limit metastasis and improve patient outcomes. Importantly, EMT may also contribute to TNBC heterogeneity, emphasizing the need to investigate the detailed molecular mechanisms underlying this process.

6. Conclusions

TNBC is a highly aggressive subtype of BC, characterized by poor prognosis and limited treatment options. Despite identifying potential molecular targets, the development of effective therapies has been hindered by the complex and heterogeneous nature of TNBC, marked by phenotypic plasticity and the activation of compensatory signaling pathways that promote tumor survival, metastasis, and progression. As a result, chemotherapy remains the primary treatment, but its long-term efficacy is severely limited by acquired resistance.
A major driver of chemoresistance in TNBC is EMT, which contributes to metastatic potential and diminishes chemotherapy effectiveness by altering drug uptake or enhancing efflux mechanisms. Additional factors such as altered drug metabolism and the TME further complicate treatment, emphasizing the urgent need for novel, targeted, and personalized therapies.
To overcome chemotherapy resistance and improve patients’ outcomes, it is essential to address the molecular complexity of TNBC, particularly the interplay between EMT, drug resistance, and tumor progression. While substantial progress has been made in understanding the role of EMT, the precise molecular mechanisms driving this process and its impact on resistance still remain largely unknown. Targeting key EMT-related pathways offers promising strategies for developing more effective therapies. A deeper understanding of these mechanisms is thus crucial for designing personalized treatment approaches that enhance TNBC management, improve survival, and elevate patients’ quality of life.

Author Contributions

Conceptualization, E.B. and A.S.; software, A.O.; formal analysis, E.B. and A.O.; data curation, A.O.; writing—original draft preparation, E.B., P.M. and M.B.; writing—review and editing, E.B., P.M., A.O., E.G. and A.S.; visualization, E.B. and A.O.; funding acquisition, A.S. All authors have read and agreed to the published version of the manuscript.

Funding

This work was funded by the Medical University of Lublin, grant number DS715.

Data Availability Statement

The R code used to generate Figure 2 and Figure 3 is available upon request. This study utilized previously published data from the TCGA-BRCA dataset. The TCGA-BRCA RNA-seq dataset was downloaded from the GDC Data Portal (based on GDC data release 12) using genome reference build GRCh38.p0 (https://portal.gdc.cancer.gov (accessed on 16 November 2024)) with TCGAbiolinks. Mutation data were sourced from the Broad Institute TCGA Genome Data Analysis Center (2016) and generated using MutSig 2CV v3.1 [82].

Acknowledgments

Figure 1 and Figure 4 were created using BioRender.com under a granted license to EB.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

ABCATP-binding cassette
ALDH1Aldehyde dehydrogenase 1
ARAndrogen receptor
BCBreast cancer
BLIABasal-like immune-activated
BLISBasal-like immunosuppressed
CAFsCancer-associated fibroblasts
CHK1Checkpoint kinase 1
circRNACircular RNA
CKCytokeratin
CLDNsClaudins
CSCsCancer stem cells
CTCsCirculating tumor cells
DDRDNA damage response
DFSDisease-free survival
ECMExtracellular matrix
EGFREpidermal growth factor receptor
EMTEpithelial–mesenchymal transition
EREstrogen receptor
FAKFocal adhesion kinase
HER2Human epidermal growth factor 2
HIF-1αHypoxia-inducible factor 1-alpha
HRHormone receptor
IHCImmunohistochemistry
IMImmunomodulatory
LARLuminar androgen receptor
LEFLymphoid enhancer factor
LILabeling index
lncRNALong non-coding RNA
M/MESMesenchymal
MAPKMitogen-activated protein kinase
MDRMultidrug resistance
METMesenchymal–epithelial transition
miRNAMicroRNA
MMPMatrix metalloproteinase
MSLMesenchymal stem-like
mTORMechanistic target of rapamycin
NACTNeoadjuvant chemotherapy
ncRNANon-coding RNA
NF-κBNuclear factor kappa-B
OSOverall survival
PCDProgrammed cell death
pCRPathological complete response
p-EMTPartial epithelial–mesenchymal transition
PRProgesterone receptor
PTMsPost-translational modifications
QNBCQuadruple-negative breast cancer
RCBResidual cancer burden
TCFT-cell factor
TCGAThe Cancer Genome Atlas
TFTranscription factor
TGF-βTransforming growth factor-beta
TJTight junction
TNBCTriple-negative breast cancer
TNF-αTumor necrosis factor α-induced
VIMVimentin
WntWingless/Integrated
ZO-1Zonula occludens-1

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