One of the main causes of cancer-related death for women globally is breast cancer [1]. Many patients in remission continue to experience relapse and metastasis, which continues to be a major cause of death for BC patients despite notable advancements in diagnostic and treatment techniques [2]. With several subtypes and phases, BC is incredibly diverse and is linked to a range of clinical outcomes and therapeutic responses [3]. These subtypes are primarily identified using immunohistochemistry (IHC) [4] and gene expression profiling [5]. Based on IHC/fluorescence in situ hybridization (FISH) analyses, BC is classified into subtypes according to the presence of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2) [3]. The molecular traits of these BC subtypes are depicted in Figure 1. Because of its propensity for early metastasis and the lack of effective targeted therapies at this time, TNBC which makes up around 20% of all BC cases has the worst prognosis and the lowest survival rates among the three IHC subtypes [6].
Despite significant advancements in BC diagnosis and therapy, current therapeutic approaches are only partially effective for individuals who come with metastatic BC or who have illness recurrence. Deeper understanding of the mechanisms underlying metastatic BC and the creation of more potent treatments are therefore desperately needed. BC is categorized into various subtypes based on distinct gene expression patterns and histological characteristics [7], and ongoing research aims to uncover the genetic mutations that contribute to tumor initiation and metastasis [8]. Nonetheless, BC results from the intricate interaction of environmental factors, including aspects connected to lifestyle, and hereditary ones. These genetic and environmental factors converge to create significant heterogeneity, which is a major driver of tumor variability. This variation occurs within a single tumor as well as between tumors in various people [9]. New studies employing "omics" technologies, such single-cell DNA and RNA sequencing, are illuminating BC heterogeneity by pinpointing particular cell populations correlated with metastasis and treatment resistance. Noteworthy progress in this field has been made through single-cell sequencing studies, which have revealed the dynamic responses to neoadjuvant chemotherapy in TNBC and identified chemoresistance signatures that can forecast the long-term results of patients [10].
Cancer stem cells (CSCs) simultaneously contribute to and result from tumor heterogeneity. They add to this heterogeneity through their high plasticity, giving rise to cells with diverse phenotypic, functional, and metabolic characteristics. At the same time, they react to numerous micro- and macro-environmental signals, which reflect the complexity of the tumor microenvironment (TME) [11]. In order to self-renew, withstand chemotherapy and radiation, and promote the development of distant metastases, CSCs take advantage of their interactions with the (TME) [12]. In particular, the CSC population is constantly influenced and maintained by non-tumor cells in the microenvironment, such as immune cells and niche components [13]. The ability of CSCs to transition between quiescent and proliferative phases, maximizing survival, demonstrates their adaptability. It has been demonstrated that quiescent CSCs can resist severe environments, elude anticancer treatments, and elude immune identification [11]. Quiescent CSCs are seen in BC and other cancers prior to treatment, build up following radio-chemotherapy, circulate in the bloodstream as circulating tumor cells (CTCs), and can remain in premetastatic areas as disseminated tumor cells (DTCs) for up to 20 years. A characteristic of CSCs is their capacity to dormancy, which is mediated by molecular pathways that are yet poorly understood. Understanding BC dormancy is essential for improving treatment outcomes and avoiding late-stage metastatic relapses, especially in BC that is estrogen receptor (ER)-positive [14]. We provide a review about the origin and microenvironments of BCSC in this review.  Lastly, we go over the clinical significance of BCSC and several treatment approaches meant to increase BC patients' metastasis-free survival.

The mammary gland is a distinctive organ that undergoes significant remodeling and differentiation well into adulthood [15]. During phases like puberty, pregnancy, and nursing, it exhibits distinct developmental changes. The mammary gland goes through cycles of cell division, proliferation, and programmed cell death with every pregnancy, wherein alveolar ducts form and expand, specialize for milk production, and then, following lactation, cease function and revert to a pre-pregnancy state. This cycle indicates that mammary stem cells play a critical part in enabling this regenerative ability [16]. Multiple studies have confirmed the presence of stem-like cells in normal breast tissue [17]. These undifferentiated cells have the potential to self-renew and develop into myoepithelial, ductal, and alveolar epithelial cells. Furthermore, there are notable parallels between the gene expression patterns of mammary stem cells and those of embryonic, neuronal, and hematopoietic stem cells [18].
The origin of BCSCs remains a topic of active debate (Figure 2). One widely discussed hypothesis indicates that BCSCs may arise from normal mammary stem cells whose regular self-renewal processes have become deregulated. Evidence shows that normal mammary stem cells and BCSCs share several key traits, including telomerase activity, self-renewal capacity, differentiation ability, resistance to apoptosis, and the ability to migrate to specific locations [19]. Given that stem cells possess intrinsic mechanisms for self-renewal, they may need fewer mutations to sustain this ability than differentiated cells, which would require additional changes to activate self-renewal inappropriately [20]. Furthermore, the longer lifespan of mammary stem cells increases the likelihood of mutation accumulation, potentially leading these cells to moderately evolve into BCSCs. Another speculation proposes that BCSCs could originate from differentiated cells, though the underlying mechanism remains uncertain [21]. This was corroborated by Guo et al. (2012), who showed that the simultaneous transient expression of exogenous Slug and Sox9 was sufficient to transform differentiated luminal cells into mammary stem cells with the capacity to continuously replenish the mammary glands [22]. This notion was further reinforced by findings from Koren et al. (2015), which showed that when the mutation PIK3CAH1047R was expressed, lineage-committed basal Lgr5-positive and luminal keratin-8-positive cells in the adult mouse mammary gland dedifferentiated into a multipotent stem-like state [23].

BCSCs are impacted and controlled by a number of variables in their milieu, much like normal stem cells are by the niche or surrounding microenvironment. These comprise physical and chemical components such as oxygen levels, food availability, and pH balance, as well as fibroblast-derived signals, autocrine signaling, and extracellular matrix (ECM) elements [24]. BCSC survival and metastatic potential are strongly impacted by growth factors and cytokines liberated by tumor cells, as well as immune cells and cancer-associated fibroblasts [24-26]. For instance, it has been found that an inflammatory loop involving interleukin-6 (IL-6) promotes trastuzumab resistance in HER2+ breast cancer by increasing the number of cancer stem cells. In both in vitro and xenograft models, according to Ginestier et al. (2010), blocking CXCR1 stopped tumor growth and precisely targeted human BCSCs [27, 28]. Disruption of the stem cell niche by carcinogenic factors may thus drive transformation and influence the final subtype of breast tumors [28], underscoring the ability of targeting the BCSC niche as a therapeutic strategy against cancer. However, this approach remains underexplored [29].

The expression of signature surface markers mainly CD44, CD24, and ALDH1+, which are generally acknowledged as important biomarkers for the BCSC phenotype, can be used to identify BCSCs, even if there are currently no universal markers for these cells [30]. Tumors with genetic diversity comparable to the original tumor were formed in SCID mice transplanted with a small population (100 cells) of these BCSCs (CD44+/CD24-/Lin-). This demonstrates how CSCs contribute to tumor spread, recurrence, and treatment resistance [31]. Clinical evidence indicates that cells expressing CD44+CD24-/Low and ALDH1+ are associated with higher tumorigenicity and correlate with lower survival rates in patients [32].
Maintaining the BCSC population requires CD44, a transmembrane glycoprotein that acts as a receptor for several growth factors and ligands in the extracellular matrix, to activate the Ras-MAPK and PI3K/AKT signaling pathways. Furthermore, CD44 triggers the p62-associated nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, which shows the treatment resistance [33-35]. Increased radioresistance and worse prognoses have been associated with NF-κB activation and CD44 expression. The CD24-/Low phenotype further promotes resistance to therapy, even though the ALDH enzyme aids in the conversion of retinol to retinoic acid, a process required for the differentiation capacities of both normal and malignant stem cells [36].
BCSCs with the CD44+/CD24-/Low surface biomarker expression exhibit a more invasive, quiescent, and basal-like phenotype, whereas BCSCs with the ALDH1+ epithelial-like phenotype exhibit a more proliferative and localized luminal characteristic [37]. BCSCs expressing both CD44+/CD24-/Low and ALDH1+ markers are associated with enhanced tumorigenic and metastatic potential [38]. Additionally, BCSCs show increased expression of the CD44 variant isoform, CD44v6, which binds to key cytokines in the TME, promoting cancer progression, cell migration, and invasion [39]. CD133, CD49f, CD61, and CD29 are additional markers for BCSCs and are also present on normal mammary stem cells (MaSCs) (Figure 3). Combining these markers with CD44+/CD24-/Low/ALDH1+ expression provides a valuable approach for isolating BCSCs and may serve as useful prognostic indicators [40].

BCSCs are pivotal due to their high tumorigenicity, along with their abilities for self-renewal and differentiation, enabling them to establish or replenish diverse cancer cell populations. Furthermore, BCSCs exhibit significant resistance to conventional chemotherapy, and treatment may even lead to an enrichment of the BCSC population, making them largely responsible for tumor recurrence [41, 42]. Lee et al. showed in their clinical investigations that following chemotherapy treatment, the CD44+CD24− population becomes enriched in initial breast cancers [43]. In a similar vein, Creighton et al. found that, in a cohort of 52 BC patients enrolled in phase II clinical trials, the CD44+CD24− population in residual tumor tissue after endocrine therapy was higher than pre-treatment samples [44]. Numerous clinical investigations demonstrate a connection between BCSCs and metastasis in addition to their role in chemoresistance and tumor recurrence. For instance, the presence of distant metastases, including bone and pleural metastases, and the early diffusion of cancer cells into the bone marrow were connected to initial tumors from individuals with BC who had high levels of CD44+CD24− [45, 46]. Additionally, the expression of ALDH1, particularly the ALDH1A3 isoform, was found to correlate significantly with aggressive clinical and pathological features [47] and with distant metastases in inflammatory BC [48]. This implies a clear correlation between the incidence of CSCs and the advancement of the disease. A study recently examined the expression of five distinct BCSC indicators (integrin subunit α6, cadherin-3, EpCAM, ALDH1, and CD44) and discovered that each biomarker was significantly more abundant in brain metastases of human BC than in unmatched main tumors. Notably, the research found that three to five of these BCSC markers were expressed simultaneously, indicating an enhanced stem cell signature. Although this BCSC signature was present in just 9.3% of initial breast tumors, it was significantly more prevalent in brain metastases of breast cancer, reaching 55.6%. Despite the fact that only a tiny percentage of original tumors had the BCSC signature, these instances were substantially associated with adverse clinical and pathological characteristics as well as lower patient survival rates for BC [49]. Therefore, research focused on BCSCs in metastatic settings is a pressing area in oncology, encompassing the discovery of unique BCSC biomarkers and models to investigate this clinically significant population. Genomic approaches could provide valuable insights for more accurately identifying BCSCs, as previously demonstrated [50]. However, these methods may not be as effective for drug targeting, as they identify a wide range of genes that are not necessarily actionable compared to cell surface biomarkers.
Cancer patients' risk assessment and treatment choices can be greatly improved by the creation of BCSC-based tools for prognosis prediction and practical application. Alternative biomarker-based techniques are to be investigated in light of the difficulties in acquiring serial samples from metastatic locations. For instance, some studies have shown that finding BCSC indicators in circulating tumor cells may serve as a stand-in for anti-CSC action [51]. In summary, designing new therapeutic strategies that specifically target CSCs could lead to more effective cancer treatments and help overcome therapy resistance.
Importantly, therapeutic targeting of BCSCs can be approached through various strategies, including targeting cell surface, cytoplasmic, and nuclear BCSC markers. Differentiation therapies and immunotherapy may also be effective ways to combat BCSCs' resistance to traditional medicines [52]. According to reviews by Saygin et al. [41] and Yang et al. [53], a number of BCSC-targeting treatments are presently undergoing clinical trials for different forms of cancer.

One interesting method for improving the selectivity of delivery systems targeted at particular cell types is the biological functionalization of nanocarriers [54]. These delivery methods usually contain agents that are able to identify and attach to the surface markers of BCSCs. One such marker, the CD44 receptor, is highly expressed on BCSCs [21]. Consequently, CD44 is often chosen as the target receptor for nanosystems aimed at BCSC targeting. For instance, scientists developed anti-CD44 antibodies functionalized with poly[(D,L-lactide-co-glycolide)-co-PEG] (PLGA-co-PEG) micelles loaded with paclitaxel (PTX), which successfully increased PTX internalization in BCSCs [55]. Additionally, for the targeted treatment of CD44+ cancer cells, gemcitabine derivatives loaded onto multifunctionalized iron oxide magnetic nanoparticles (MNPs) linked with anti-CD44 antibodies were created [54]. These nanoparticles demonstrated good targeting, and the reduction of CD44+ cancer cells in pancreatic and BC cell lines validated the possibility of selective drug delivery.
One ligand that has been found to specifically bind to CD44 is hyaluronic acid (HA) [56]. In contrast to normal tissues, BC cells have a noticeably increased absorption of HA, which is necessary to sustain high levels of P-glycoprotein (P-gp) production, a major cause of multidrug resistance [57]. Because of this property, HA is a desirable targeting moiety for anti-BCSC nanomedicines. Choleryl-hyaluronic acid (CHA) nanogel-drug conjugates were developed by Wei et al. (2013) with the express purpose of effectively treating cancer cells [58]. Through endocytosis mediated by the CD44 receptor, these nanogels were effectively ingested while concurrently engaging with the membrane of the cancer cell. Additionally, the cellular absorption of salinomycin (SLM) nanoparticles was increased by 1.5 times upon functionalization with HA coating [59].
Wang et al. (2013) developed a HA-mediated BCSC-targeting delivery system consisting of lipid bilayer-supported HA-MSS (Hyaluronan-modified mesoporous silicon nanoparticles) loaded with 8-hydroxyquinoline [60]. Their findings indicated that HA stimulated the adoption of HA-MSS in BCSCs. Furthermore, Ganesh et al. (2013) developed a number of HA-based self-assembling nanosystems that target CD44 for the delivery of siRNA. They identified increased gene silencing activity and siRNA delivery efficiency in drug-resistant tumor models with overexpressed CD44 receptors [61]. They discovered that siRNAs may be transfected into cancer cells with high CD44 expression using a variety of HA derivatives. It's interesting to note that high level of soluble HA may block CD44 receptors, which would limit cellular uptake by over 90% [61]. With the intention of targeting BCSCs, Chen et al. (2015) developed new multifunctionalized hyaluronan oligosaccharides-histidine-menthone 1,2-glycerol ketal (oHM) conjugates. Hyaluronan oligosaccharides are used by these oHM conjugates, which take the form of micelles, to bind selectively to the CD44 receptor found on BCSCs [62].
Chitosan’s chemical structure partially resembles that of hyaluronic acid (HA), but unlike HA, chitosan carries a positive charge, which may enhance the binding efficiency of chitosan-modified nanoparticles to mammalian cells. In order to specifically target CD44 receptors on BCSCs, Rao et al. (2015) developed doxorubicin-loaded polymeric nanoparticles coated with chitosan. When compared to the free drug, these tailored nanoparticles enhanced doxorubicin's ability to eradicate BCSCs by a factor of six [63]. With a focus on CD133 as a target receptor, Swaminathan et al. (2013) created polymeric nanoparticles modified with paclitaxel loaded anti-CD133 antibodies. Their study found that these nanoparticles effectively eliminated BCSCs in vitro and significantly decreased tumor formation in vivo, indicating that CD133 may be a promising target for anti-BCSC therapies [64].
For the active targeting of BCSCs, a number of other targets can be chosen in addition to the CD44 and CD133 receptors. BCSC population exhibits much higher expression of vasoactive intestinal peptide (VIP) receptors, which makes VIP a promising active targeting moiety for improving anti-BCSC efficacy [65]. It has been demonstrated that a new delivery system incorporating sterically stabilized curcumin phospholipid nanomicelles (C-SSM) conjugated with VIP efficiently suppresses the proliferation of BC cells that contain BCSCs [65].
Aydın (2013) used Herceptin (HER) as the targeted ligand for PLGA nanoparticles loaded with salinomycin (SAL), which enhanced the binding and accumulation of SAL in BC cells. Human epidermal growth factor receptor type 2 (HER2)-positive metastatic breast tumors, which overexpress HER2 in 25–30% of invasive breast cancers, can be treated with the authorized antibody HER. Targeting SAL to the bulk of BC may lead to a notable decrease in BCSCs because SAL suppresses the growth of BC and selectively removes human BCSCs from tumorspheres [66].

The overexpression of ATP-binding cassette (ABC) transporters, increased aldehyde dehydrogenase (ALDH) activity, improved DNA repair processes, improved scavenging of reactive oxygen species (ROS), evasion of cell death, induction of dormancy, autophagy, and possibly other resistance mechanisms that are still poorly understood are some of the mechanisms that BCSCs use to withstand drugs, according to mounting evidence. ABC transporters transfer a variety of substrates across cellular membranes by using the energy produced by ATP binding and hydrolysis. Because they regulate the efflux of numerous anticancer medications [67]. Moreover, they are increasingly acknowledged for their role in managing various functions that bolster malignant metabolism [68]. Britton et al. found that stem cells resistant to mitoxantrone in BC expressed more ABCG2 (also called BC resistance protein, or BCRP) than non-stem cancer cells [69]. Currently, the SOX2-ABCG2-TWIST1 axis has been demonstrated to enhance stemness and chemoresistance in triple-negative breast cancer (TNBC), suggesting that ABC proteins could serve as promising targets for the eradication of BCSCs [70]. One of the earliest markers used to identify BCSCs was ALDH1, one of the enzymes in the ALDH family that aid in the conversion of intracellular aldehydes into carboxylic acids [71]. Numerous studies have linked chemoresistance to elevated levels of ALDH family members [72]. Croker et al. found that ALDHhi CD44+ BC cells contribute to resistance against both chemotherapy and radiation, and inhibiting ALDHs sensitizes BCSCs to chemotherapy [73]. Numerous experiments have explored the correlation between aldehyde dehydrogenases (ALDHs) and BC prognosis, revealing inconsistent results. These discrepancies may be attributed to the heterogeneity of BC and the notion that ALDH1 may have distinct roles across various BC subtypes. Specifically, it has been reported that ALDH1 expression significantly influences the prognosis of luminal type breast cancer [74]. Another key mechanism by which BCSCs develop therapy resistance is through enhanced DNA repair capabilities. According to early study by Philips et al., BCSCs are better at repairing DNA after radiation and produce fewer reactive oxygen species (ROS) than non-stem BC cells [75]. Further research revealed that BCSCs in human and mouse tumors had lower ROS levels than their non-tumorigenic counterparts, show less DNA damage, and are more protected following radiation exposure. Enhanced expression of free radical scavenging systems is associated with decreased ROS levels in BCSCs; pharmacological depletion of these scavengers has been shown to decrease BCSC clonogenic potential, resulting in radiosensitization [76]. It has been demonstrated that constitutive signaling between PERK and NRF2 protects BCSCs from chemotherapy by increasing drug efflux and reducing ROS levels, which makes it a possible target for chemotherapy sensitization of drug-resistant cells [77].
DNA repair genes are upregulated in BCSCs, along with improved reactive oxygen species (ROS) scavenging systems. The transcriptional profile of BCSCs extracted from the mammary glands of p53-null mice brought this to light [78]. These BCSC populations are crucial for the formation of chemoresistance, clonal evolution, and tumor progression after chemotherapy, and they have also been linked to resistance to platinum-based chemotherapy in a mouse mammary tumor model with a BRCA1/p53 mutation [79]. Autophagy has become a prominent response to chemotherapeutic drugs in CSCs throughout the last ten years. In order to maintain energy balance during nutritional shortage, stress, pathogen exposure, or hypoxia, autophagy was first discovered to be a catabolic process that controls cell survival and dormancy [80]. Later studies have linked autophagy to resistance to treatment in CSCs and tumor cells [81]. However, autophagy can have dual roles; it may suppress tumorigenesis in certain contexts while promoting it in others [82]. Autophagy has been shown to be vital for the tumorigenic capabilities of BCSCs [83] and is considered a key element of the pro-survival approaches employed by these cells, particularly in challenging tissue microenvironments associated with nutrient scarcity, cytotoxic treatments, and metastatic spread [82, 84]. The significance of autophagy in the survival strategies of BCSCs is particularly notable in the premetastatic phase, where disseminated BC cells can remain dormant for years or even decades before re-emerging as highly aggressive secondary tumors. Recent research has revealed that BCSCs are disseminated tumor cells (DTCs) with the capability to form recurrent metastatic lesions and survive metastatic dormancy [85]. Through a number of processes, including stimulation of autophagic pathways, BCSCs exhibit dormant phenotypes during metastatic latency, which is essential for their survival and capacity for metastasis [86]. Autophagy facilitates BCSC survival at metastatic sites by enabling these cells to evade apoptotic signals and withstand chemotherapeutic treatments. For instance, it increases p53 activity and DNA repair via autophagy-related 7 (ATG7) [88] and promotes SRC-mediated TRAIL resistance in bone metastases [87]. Additionally, new research has shown that the autophagy machinery keeps 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) expression low, which helps keep metastatic BC cells dormant. The aberrant expression of PFKFB3 in dormant BCSCs is restored by targeted reduction of autophagic factors that physically interact with PFKFB3, such as ATG3, ATG7, or p62/sequestosome-1. Proliferative pathways are reactivated as a result of this repair, and metastatic expansion follows [89]. Studies demonstrating the function of Spleen Tyrosine Kinase (SYK) in the epithelial-to-mesenchymal transition (EMT) required for BC metastasis have provided more proof of connection between autophagy and metastatic dormancy. It was discovered that SYK which is located within cytoplasmic RNA processing structures called P-bodies, is significantly expressed in cells going through EMT. During the mesenchymal-to-epithelial transition (MET), autophagy-mediated P-body clearance depends on SYK activity. By preventing the clearance of P-bodies and MET, either pharmacologically blocking SYK with fostamatinib or genetically knocking out ATG7 inhibited the growth of metastatic tumors [90].
Autophagy affects tumor immunosurveillance in a number of ways as well as controlling the plasticity and dormancy of BCSCs. On the one hand, autophagy can reduce the anti-tumor immune responses that are mediated by CTLs and NK cells [91]. On the other hand, it may be involved in the development of certain immune cells and is essential for antigen presentation to T cells [91]. Together with the limited potency and effectiveness of many investigated anti-autophagic drugs, this dual role of autophagy in tumor immune modulation may help to explain the difficulties encountered in the clinical usage of autophagy inhibitors [92]. Finally, hypoxia signaling and the hypoxia-induced dormancy pathway in BC are intimately linked to autophagy. Chemotherapy can also cause hypoxic reactions, which set off a chain of events that increases BCSCs by releasing calcium from the endoplasmic reticulum and upregulating pluripotency genes [93].

Because BCSCs are resilient and can disseminate, metastasis, and tolerate therapies, BC still poses a substantial concern despite tremendous progress in diagnosis and treatment over the past 20 years. Converting ongoing basic and preclinical research on BCSC biology into therapeutic applications is essential to improving the efficacy of current cancer treatments. It is crucial to address many facets of BCSC biology in order to successfully design treatments meant to eradicate these cells. The targeting tactics used in current anti-BCSC medications present a significant difficulty since they frequently concentrate on transcriptional factors and intracellular signaling pathways associated with stemness, which overlap with those of normal stem cells and are therefore challenging to target. The need for novel inhibitors is further highlighted by the lack of specificity of current treatments that target BCSC signaling. Finding novel, promising indicators that are easily used in clinical settings is therefore essential. There is substantial clinical significance in the investigation of potential BCSC biomarkers and the identification of distinct pathways peculiar to this cell subgroup.

Acknowledgements

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Author contributions

BC contributed to draft, critical revision of the article and approved the final submission; MWA contributed to the revision and figure production.
Competing interests

I declare that there is no conflict of interest regarding the publication of this document.

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