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Molecular Characteristics of TNBC: Comparison
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Please note this is a comparison between Version 2 by Conner Chen and Version 1 by Liliana-Roxana Balahura (Stamat).

Researchers have investigated the molecular mechanisms of breast cancer initiation and progression, especially triple-negative breast cancer (TNBC), in order to identify specific biomarkers that could serve as feasible targets for innovative therapeutic strategies development. TNBC is characterized by a dynamic and aggressive nature, due to the absence of estrogen, progesterone and human epidermal growth factor 2 receptors.

  • triple-negative breast cancer
  • inflammasome
  • pyroptosis

1. Introduction

The breast is a complex structure, which is organized in 15 to 25 lobes of different sizes that are connected with lactiferous ducts that terminate in the nipple, ductal formations and glandular tissue, all of these being surrounded by fibro-adipose tissue [1]. Specifically, the adult breast is a tissue highly variable in conformation, adiposity and volume, due to the different proportions between adipose, fibrous and glandular tissue, among which are also found blood and lymphatic vessels. The corresponding distribution of fat and collagenous components differs among women and is influenced by hormonal, physiologic and environmental factors [2].
Breast cancer (BC) is a dynamic, aggressive and heterogeneous disease that is the principle cause of death among women worldwide, but that also affects men [3]. This neoplasm has the potential to be determined by exposure to both genetic and non-genetic risk factors such as gender, age, menopause, nulliparity, obesity, alcohol abuse and exposure to hormones, radiation or therapy [1]. The early detection and diagnosis of BC is based on screening techniques (ultrasound, mammography, contrast-enhanced digital mammography, magnetic resonance imaging and positron emission tomography), microwave imaging techniques (microwave tomographic, radar-based microwave imaging and radiometry), biomarker-based techniques (radioimmunoassay, immunohistochemistry, enzyme-linked immunosorbent assay and fluoroimmunoassay) and breast tissue biopsies, which are used to differentiate between malign and benign tumors [4].
Following a diagnosis of BC, it is necessary to stage it according to the American Joint Committee on Cancer (AJCC) tumor, nodes, and metastasis (TNM) system, as TNM staging is used to define and stratify the size of the tumors (T), the status of regional lymph nodes (N), and distant metastasis (M) [5]. TNM staging is divided into four classes: (I) clinical staging, which includes information from clinical examination; (II) pathological staging, which includes the affected anatomical formations; (III) post-therapy staging, which includes clinical and pathologic information; and (IV) restaging, if necessary [6].
In order to establish the most efficient treatment for patients, the histological classification is completed via the molecular classification of BC that is based on the expression profiles of the estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and Ki67 antigen. The main molecular subtypes of breast cancer are luminal A (ER positive, PR positive and HER2 negative), luminal B (ER positive, PR negative and HER2 negative), HER2-enriched (ER negative, PR negative and HER2 positive), triple-negative breast cancer (TNBC), basal-like (ER negative, PR negative and HER2 negative), claudin low (ER negative, claudin negative, vimentin positive, E-cadherin low) and normal breast-like (adipose tissue gene signature) [7]. Luminal and HER2-enriched subtypes are associated with good prognoses and are highly responsive to therapy, resulting in a greatly improved outcome, while TNBC is the most aggressive subtype of BC, which is characterized by a high cell proliferation rate and a tendency to relapse [8]. Experimental studies indicate the presence of two main pathways involved in low-grade and high-grade breast tumorigenesis; low-grade BCs are regularly ER positive, PR positive and HER2 negative, while high-grade BCs are ER negative, PR negative and HER2 positive [9].
The mechanism of BC is dependent on the genetic modification and molecular processes that determine initiation, transformation and progression from normal tissue to tumor tissue [10]. More than 90% of diagnosed BCs are associated with the mutation of specific genes, such as breast cancer genes 1 and 2 (BRCA1 and BRCA2), TP53, phosphatase and tensin homolog (PTEN), serine/threonine kinase 11 (STK11), ataxia-telangiectasia mutated (ATM), BRCA1 interacting protein 1 (BRIP1) or the partner and localizer of BRCA2 (PALB2), etc. [11].
In addition, BC aggressiveness is supported by chronic inflammation considering the up-regulation of pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, IL-18 or tumor necrosis factor-α (TNF-α), growth factors or free radicals [12]. The secretion and release of pro-inflammatory cytokines are associated with inflammasome complex activation. Inflammasome is a cytoplasmic multiprotein complex, composed of a sensor (NOD-like receptor protein (NLRP)), an adaptor (an apoptosis-associated speck-like protein containing a caspase-activation and recruitment domain (CARD) (ASC)) and effector molecules (pro-caspase). The inflammasome complex is involved in numerous physiological and pathological mechanisms, including different types of cancer, although the activation of this complex can have both a positive or negative impact on carcinogenesis [13]. First of all, inflammasome activity stimulates epithelial mesenchymal transition (EMT), metastasis and angiogenesis, while inhibiting apoptosis and enhancing tumor development. On the other hand, the inflammasome pathway is also associated with immune reactions and the programmed death of tumor cells through pyroptosis [14].
The dynamic interaction between BC and inflammasome is regulated by a complex molecular network, including non-coding RNAs (ncRNAs). NcRNAs can be classified into short non-coding RNAs (sncRNAs) or long non-coding RNAs (lncRNAs), based on their number of nucleotides [15]. Among the most studied sncRNAs are microRNAs (miRNAs), which are single-stranded ribonucleic acid molecules involved in diverse cellular processes (cell survival, proliferation and adhesion, motility, cell death, inflammation, carcinogenesis, etc.). According to their implication in tumorigenic mechanisms and metastasis, miRNA molecules can be classified into oncogenic miRNAs and suppressor miRNAs [16]. Increasing evidence has indicated that many miRNAs are involved in the regulation of the inflammasome complex (miR-7, miR-9, miR-20a, miR-21, miR-23a, miR-30e, miR-33, miR-132, miR-133, miR-146, miR-155, miR-223, miR-296, miR-377, miR-711, etc.) and that these molecules represent a link between inflammasome activity and BC, especially TNBC [17]. Recently, researchers’ attention has been directed towards targeting these molecules as possible therapeutic strategies for the treatment of BC, due to their significance in post-transcriptional regulation [18].

2. Molecular Characteristics of TNBC

TNBC is a highly invasive and aggressive type of BC, which is characterized by the absence of ER, PR and HER2 expression. TNBC represents almost 20% of all diagnosed BC, being associated with resistance to chemotherapy, a predisposition to metastasis, poor prognoses and reduced survival rates [19]. Over the years, researchers have studied the molecular signatures of TNBC using advanced techniques and, according to gene expression profiles, Lehmann et al. [20], Burstein et al. [21] and Jezequel et al. [22] have all proposed different classification of TNBC in order to investigate possible therapeutic targets to improve the outcomes of TNBC (Table 1). Moreover, according to Lehmann et al., TNBC can be subdivided into six groups: basal-like 1, basal-like 2, mesenchymal, mesenchymal stem-like, immunomodulatory, and luminal androgen receptor TNBC [20]. Burstein et al. proposed a TNBC classification divided into four subtypes: basal-like immune-activated, basal-like immune-suppressed, mesenchymal, and luminal androgen receptor TNBC [21], while Jezequel et al. divided triple-negative tumors into three clusters: C1 (22.4%), C2 (44.9%) and C3 (32.7%) [22]. Classifying and understanding the particularities of TNBC allow for the development of personalized medicine, because each subtype has different characteristics and responses to anti-tumor therapy [23].
Table 1.
Molecular comparison between three proposed classifications of TNBC.
TNBC Classification Method of Analyses Number of Patients Subtypes Abnormal Mechanisms Relevant Markers Therapeutic Strategies Refs.
The Vanderbilt Subtype K-means clustering 586 Basal-like 1 Cell cycle

Cell proliferation

DNA damage response		 MYC, PIK3CA, CDK6, AKT2, KRAS, FGFR1, IGF1R, CCNE1, CDKN2A/B, BRCA2, PTEN, MDM2, RB1, TP53, KI67 PARP inhibitors

HDAC/DNMT inhibitors

Natural-killer therapy

Cisplatin,		 [20,24,25,26][20][24][25][26]
Basal-like 2 EGFR, MET, NGF, Wnt/β-catenin, TP63,

IGF1R signaling pathway

Glycolysis

Gluconeogenesis		 TP53, TP63, EGFR, MET, BRCA1, RB1, PTEN, CDKN2A, UTX mTOR inhibitors

Growth factor inhibitors (lapatinib, gefitinib, cetuximab, etc.)		 [20,24,27][20][24][27]
Immunomodulatory Th1/2, IL-7, IL-12 signaling pathway TP53, CTNNA1, DDX18, HUWE1, NFKBIA, APC, BRAF, MAP K4, RB1, CTLA4, PDL1 PD1/PDL1/CTLA4 inhibitors

Cisplatin
[47]. In close correlation with the development of inflammatory reactions and TNBC is the activation of the NLRP3 (pyrin domain-containing protein 3) inflammasome complex, with IL-1β and IL-18 being the two major cytokines activated by NLRP3 inflammasome, which promote tumor cell proliferation and invasion [48]. Over the years, new signaling pathways within breast TME have been discovered, which have opened up new perspectives for the development of strategies that aim to block these signals that promote tumorigenesis, angiogenesis and metastasis. Specifically, conventional therapeutic strategies are the gold standard for neoadjuvant treatment represented by a combination between anthracyclines and taxanes, capecitabine and taxane and ixabepilone monotherapy (paclitaxel, 5-fluorouracil, doxorubicin, cisplatin, carboplatin, abraxane, bevacizumab, cyclophosphamide, ixabepilone, capecitabine, etc.), adjuvant treatment (anthracycline-based drugs), surgery (mastectomy and lumpectomy) and radiotherapy [49]. Despite the heterogeneity and aggressiveness of TNBC, the corresponding standard of care (SOC) requires neoadjuvant chemotherapy, followed by surgery and adjuvant chemotherapy (Table 2). There are several treatment schemes for early diagnosed TNBC that are based on anthracycline and taxane administration, but which cause numerous adverse effects (nausea, fatigue, gastrointestinal toxicity, myelosuppression, alopecia, hypothyroidism, hyperthyroidism, pneumonitis, skin reactions, adrenal insufficiency, peripheral neuropathy, neutropenia, pyrexia, anemia, thrombocytopenia, electrolyte abnormalities, infection, etc.) and do not lower the relapse rate [50].
Table 2.
SOC for TNBC.
Approach Class of Agents Examples of Therapy Mechanism of Action Refs.
Neoadjuvant Anthracycline + Taxane Doxorubicin + Cyclophosphamide + Paclitaxel

Epirubicin + Cyclophosphamide + Nab-paclitaxel		 Inhibition of DNA and RNA synthesis

Inhibition of topoisomerase II enzyme

Generation of reactive oxygen species (ROS)

Stabilization of microtubules		 [49,51][49][51]
Fluoropyrimidine + Taxane Capecitabine + Docetaxel


PARP inhibitors [20,24][20][24]
Mesenchymal-like
Fluoropyrimidine + Epothilone Capecitabine + Ixabepilone Cell motility

Cell proliferation

Cell differentiation

Wnt, TGFβ, Notch signaling pathway

Epithelial-mesenchymal transition		 PTEN, RB1, TP53, PIK3CA, VEGFR2, PI3KCA mTOR inhibitors

Drugs targeting epithelial–mesenchymal transition

Abl/Src inhibitor

Dasatinib		 [20,24,28][
Adjuvant
53]. Other therapeutic approaches are represented by platinum salts (carboplatin, cisplatin, etc.) immunotherapies that target the programmed cell death-1 (PD-1) receptor/PD-L1 pathway, immune-checkpoint inhibitors, poly-adenosine diphosphate ribose polymerase (PARP) inhibitors or AKT inhibitors [54].
Table 3.
Novel strategies for TNBC treatment.
Class of Agents Examples of Therapy Mechanism of Action Refs.
PD-1 and PD-L1 inhibitors Pembrolizumab + Paclitaxel

Doxorubicin + Cyclophosphamide

Pembrolizumab + Paclitaxel + Carboplatin

Durvalumab + Nab-paclitaxel

Atezolizumab + Nab-paclitaxel

Atezolizumab + Nab-paclitaxel + Carboplatin		 Reactivation of the anti-tumor immune response

PD-1/PD-L1 complex formation inhibition		 [55]
Platinum-based therapy Carboplatin + Eribulin

Gemcitabine + Carboplatin + Iniparib

Carboplatin + Bevacizumab

Cisplatin + Paclitaxel + Everolimus

Paclitaxel + Carboplatin		 Double-strand DNA break

Apoptosis initiation		 [56,57,58][56][57][58]
Cell cycle inhibitors Trilaciclib, etoposide, abemaciclib, prexasertib Activate the spindle assembly/mitotic checkpoint

Prolonged mitotic arrest

Cell death initiation		 [59]
Anthracycline + Taxane Doxorubicin + Cyclophosphamide + Docetaxel [49,52][49][52]20][24][28]
Mesenchymal stem-like Cell motility

Cell differentiation

Growth factor signaling

Epithelial–mesenchymal transition

Low proliferation		 ABCA8, PROCR, ENG, ALDHA1, PER1, ABCB1, TERT2IP, BCL2, BMP2, THY, HOXA5, HOXA10, MEIS1, MEIS2, MEOX1, MEOX2, MSX1, BMP2, ENG, ITGAV, KDR, NGFR, NT5E, PDGFR, THY1, VCAM1, VEGFR2 mTOR/MEK/PI3K inhibitors,

Src antagonists Antiangiogenic drugs
PI3K/AKT/mTOR inhibitors

Abl/Src inhibitor

Dasatinib		 [ Rapamycin, ipatasertip, buparlisib, pictilisib, alpelisib Cancer cells migration and invasion inhibition

Apoptosis initiation20,		 [6124][20][24]
Luminal androgen receptor Steroid synthesis, porphyrin metabolism,

Androgen/estrogen metabolism		 DHCR24, CD166, FASN, FKBP5, APOD, PIP, SPDEF, CLDN8 Anti-AR therapy

PI3K/CDK4/6 inhibitors
45
]
[
20
][38][39][40][41][42][43][44][45]
Although neoadjuvant chemotherapy is the standard treatment approach for diagnosed TNBC, the therapeutic potential of other agents that interfere with various molecular mechanisms (such as angiogenesis, the immune response, the cell cycle, etc.) have been tested or are currently under testing and approval (Table 3). The optimal treatment scheme for TNBC is a great challenge due to the disease’s heterogeneity and increased risk of relapse, so the researchers have explored several promising anti-tumor agents (pembrolizumab, bevacizumab, olaparib, sacituzumab govitecan, etc.) [
Angiogenesis inhibitors
Cisplatin + Bevacizumab

Anlotinib, apatinib, afatinib, lenvatinib, erlotinib, famitinib, pyrotinib		 Blocking new blood vessel formation

Tumor growth inhibition

VEGF signaling pathway disruption		 [60]
,62][61][62]
PARP inhibitors Olaparib + Carboplatin + Paclitaxel

Veliparib + Carboplatin

Cisplatin + Rucaparib

Veliparib, niraparib, talazoparib		 Double-strand DNA break

Cell death initiation

Base excision repair

Relax/condense chromatin bind nucleosom PARylate H1/H2B		[20,24,26 [63],29][20][24][26][29]
The Baylor Subtype Non-negative matrix factorization 198 Luminal androgen receptor Steroid hormone biosynthesis

Porphyrin and chlorophyll metabolism

PPAR signaling pathway

Androgen and estrogen metabolism

Hormonale-mediated signaling		 TP53, PI3KCA, AKT1, ERBB2, ERBB4, CDK4/6, AR, MUC1, ER, CDH1, KRT7, KRT8, KRT18, KRT19, XBP1, FOXA1 Anti-AR/MUC1 therapy [21,
EGFR inhibitors Bintrafusp Alfa, dasatinib, geftinib, sorafenib, nimotuzumab, panitumumab, erlotinib, osimertinib Cell death initiation

Inhibition of cancer cell proliferation

Blocking dimerization of receptors, auto-phosphorylation and downstream signaling

Inducing receptor internalization, degradation and stable downregulation		30,31,32,33 [64],34][21][30][31][32][33][34]
Mesenchymal Cell motility

Epithelial–mesenchymal transition

Focal adhesion

TGF-β signaling pathway

Adipocytokine signaling pathway		 PIK3CA, PTEN, STAT3, IGF1, prostaglandin, TGF-β, Wnt, β-catenin, PDGFRα, c-Kit, ABC transporter
Androgen receptor (AR) antagonists Bicalutamide, enzalutamide, abiraterone, palbociclib Decrease in cancer cell viability

G1 phase arrest

Apoptosis induction		TKI/RAS/mTOR inhibitor

Growth factor inhibitors		 [30,][30]65[65][21,30,31,32,33][21][30][31][32][33]
Basal-like immunosuppressed Mitotic cell cycle

Mitotic prometaphase

M phase of mitotic cell cycle

DNA replication

DNA repair

Immune response

Antibody drug conjugatesInnate immune response VTCN1, TP53, CENPF,

BUB1, PRC1, VTCN1, MS4A6A, MTBP, FGFR2, BARD1, RNASE6		 VTCN1 inhibition Sacituzumab govitecan,

Ladiratuzumab vedotin,

Trastuzumab deruxtecan[21,		 Cell growth and migration inhibition

Binding to the topoisomerase in DNA replication inhibition

S-phase-specific cell death initiation

31][21][31]
DNA damage [66] Basal-like immune-activated Cytokine–cytokine receptor interaction

T cell receptor signaling pathway

B cell receptor signaling pathway

Chemokine signaling pathway

NF-kB signaling pathway		 CCR2, CXCL13, CXCL11, CD1C, CXCL10, CCL5, STAT Drugs targeting stat signal transduction molecules and cytokines [21,31,35][21][31][35]
The French Subtype Fuzzy clustering 194 Cluster 1 Luminal androgen receptor enriched AR, Hsp90, PI3K, FGFR4, TTN, TNR, PKHD1L1, SPTA1, NCKAP5, COL15A1, ANKRD11, MYLK Anti-AR therapy [36,37,38][36][37][38]
Cluster 2 Basal-like with low immune response

High M2-like macrophages

High pro-tumorigenic

Low anti-tumor immune response		 CCL2, CCL5, CCL18, CCL10, CXCL22, IL4, IL8, IL10, IL13, TGFβ1, CD206, CD204, VEGF, Aginase1, PIK3CA, NF1, AKT1, FBN3, ABCC1, DNHD1 M2 inhibition

Repolarization of M2 into M1 macrophages		 [20,38,39,40,41,42,43,44,Cluster 3 Basal-enriched

High immune response

Low M2-like macrophages

Low pro-tumorigenic

High anti-tumor immune response		 IL-1β, IL-6, IL-12, IL-23,CXCL9, TNF-α, CCL2, IFNγ, GSF10, DNAH1, CDH23, AHNAK2, GTF3C1 Repolarization of M2 into M1 macrophages [38,41,45][38][41][45]
Abbreviations: ATP-binding cassette (ABC), ATP-binding cassette subfamily a member 8 (ABCA8), ATP-binding cassette subfamily b member 1 (ABCB1), ATP-binding cassette subfamily c member 1 (ABCC1), tyrosine-protein kinase ABL1 (Abl), AHNAK nucleoprotein 2 (AHNAK2), protein kinase B (AKT), aldehyde dehydrogenase 1 family, member A1 (ALDHA1), ankyrin repeat domain 11 (ANKRD11), antigen-presenting cell (APC), apolipoprotein D (APOD), androgen receptor (AR), BRCA1-associated RING domain protein 1 (BARD1), B-cell lymphoma 2 (BCL2), bone morphogenetic protein 2 (BMP2), serine/threonine-protein kinase B-Raf (BRAF), breast cancer type susceptibility (BRCA), mitotic checkpoint serine/threonine-protein kinase (BUB1), chemokine (C-C motif) ligand (CCL), cyclin E1 (CCNE1), C-C chemokine receptor type 2 (CCR2), cluster of differentiation (CD), cadherin (CDH), cyclin-dependent kinases (CDK), cyclin-dependent kinase inhibitor (CDKN), centromere protein F (CENPF), claudin 8 (CLDN8), collagen type XV alpha 1 chain (COL15A1), cytotoxic T-lymphocyte associated protein 4 (CTLA4), catenin alpha 1 (CTNNA1), C-X-C motif chemokine ligand (CXCL), DEAD-box helicase 18 (DDX18), 24-dehydrocholesterol reductase (DHCR24), dynein axonemal heavy chain 1 (DNAH1), DNA methyltransferase 1 (DNMT), epidermal growth factor receptor (EGFR), endoglin (ENG), epidermal growth factor (ERBB), fatty acid synthase (FASN), fibrillin 3 (FBN3), fibroblast growth factor receptor (FGFR), FK506 binding protein 5 (FKBP5), forkhead box A1 (FOXA1), growth differentiation factor 10 (GSF10), general transcription factor IIIC subunit 1 (GTF3C1), histone deacetylase (HDAC), homeobox A cluster (HOXA), heat shock protein 90 (Hsp90), HECT, UBA and WWE domain containing 1, E3 ubiquitin protein ligase (HUWE1), interferon (IFN), insulin-like growth factor 1 (IGF1), insulin-like growth factor 1 receptor (IGF1R), interleukin (IL), integrin subunit alpha V (ITGAV), kinase insert domain receptor (KDR), marker of proliferation Ki-67 (KI67), Kirsten rat sarcoma virus (KRAS), keratin (KRT), mitogen-activated protein kinase 4 (MAPK4), mouse double minute 2 homolog (MDM2), Meis homeobox 1 (MEIS), mitogen-activated protein kinase kinase 1 (MEK), mesenchyme homeobox 1 (MEOX), tyrosine-protein kinase Met (MET), membrane spanning 4-domains A6A (MS4A6A), msh homeobox 1 (MSX1), MDM2 binding protein (MTBP), mechanistic target of rapamycin kinase (mTOR), mucin 1 (MUC1), myosin light chain kinase (MYLK), NCK associated protein 5 (NCKAP5), neurofibromatosis type 1 (NF1), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), NFKB inhibitor alpha (NFKBIA), nerve growth factor (NGF), nerve growth factor receptor (NGFR), ecto-5′-nucleotidase (NT5E), poly (ADP-ribose) polymerase (PARP), programmed cell death protein 1 (PD1), platelet-derived growth factor receptor (PDGFR), programmed death ligand 1 (PDL1), period circadian regulator 1 (PER1), phosphoinositide 3-kinase (PI3K), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), phosphatidylinositol phosphate (PIP), polycystic kidney and hepatic disease 1-like protein 1 (PKHD1L1), polycomb repressive complex 1 (PRC1), protein C receptor (PROCR), phosphatase and tensin homolog (PTEN), retinoblastoma susceptibility gene (RB1), ribonuclease a family member K6 (RNASE6), SAM pointed domain-containing Ets (SPDEF), spectrin alpha, erythrocytic 1 (SPTA1), steroid receptor coactivator (Src), signal transducer and activator of transcription (STAT), telomerase reverse transcriptase (TERT), transforming growth factor (TGF), tumor necrosis factor (TNF), tenascin-R (TNR), transient tachypnea of the newborn (TTN), ubiquitously transcribed tetratricopeptide repeat X chromosome (UTX), vascular cell adhesion molecule 1 (VCAM1), vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor 2 (VEGFR2), V-set domain-containing T-cell activation inhibitor 1 (VTCN1), wingless/integrated (Wnt), X-box binding protein 1 (XBP1).
The breast tumor microenvironment (TME) is associated with chronic inflammatory reactions, with inflammatory infiltrate being a prognostic marker of cancer. Pro-inflammatory molecules together with their specific receptors are involved in the development of TNBC due to their capability to promote cell differentiation and angiogenesis, to recruit immune cells and to influence the immune system [46]. Lymphocytes, macrophages and fibroblasts are the most common cell types of the TME and secrete different factors (such as cytokines, chemokines, enzymes, growth factors, etc.), which are associated with an aggressive malignancy and high risk of metastasis. Pro-inflammatory mediators (IL-6, CCL2, COX2, and TNF-α) are generally up-regulated in breast tumor stroma; IL-1, IL-6, IL-8, IL-11, IL-18 and IL-23 are among the most studied inflammatory factors involved in inflammation, TNBC, invasion and metastasis
The molecular characteristics of TNBC tumors (heterogeneity and the chemoresistance mechanism) raise difficulties in establishing an effective conventional therapeutic strategy; therefore advanced therapeutic strategies have been developed. There are two main types of advanced therapeutic treatments: passive transport (or enhanced permeability and retention (nanoparticles)) and active transport (miRNA and aptamers) [49].

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