The Role of HSP70 in Regulation of Breast Cancer Stem Cells and Apoptotic Pathway

1. Introduction

Breast cancer is the most prevalent cancer in women worldwide and encompasses multiple molecular subtypes. Hormonal factors, genetic predisposition, and environmental influences contribute to the development of breast cancer. According to recent data, Breast cancer is the most commonly diagnosed cancer type worldwide, and its burden has been increasing in recent years. Breast cancer, which has replaced lung cancer as the most commonly diagnosed cancer worldwide, accounts for about 30% of all female cancers, reaching a total of 2.3 million new cases in both genders. In the United States, breast cancer cases have increased every year between 2012 and 2021. This increase is especially noticeable among women under the age of 50. However, according to two separate reports by the American Cancer Society, breast cancer-related death rates have decreased by approximately 10% in the last decade. It is also emphasized that black women have lower survival rates for all types of breast cancers, except localized disease. It has been stated that the increase in cases is largely “limited to localized stage and hormone receptor-positive diseases.” The annual increase of 1.4% in women under the age of 50 was 0.7% in women aged 50 and over [1, 2].

HSP70 is a highly conserved molecular chaperone that plays an important role in maintaining cellular proteostasis under both physiological and stress conditions. Its primary functions include ensuring the folding, stabilization, and refolding of newly synthesized and misfolded proteins. In addition to these functions, HSP70 also plays a role in preventing protein aggregation and transporting proteins between cellular compartments. This versatile activity of HSP70 suggests that it is an important regulator of cellular homeostasis and survival, especially in cancer disease. In this context, HSP70 interacts with a wide range of client proteins, including many oncogenes or proteins involved in cancer progression. HSP70 increases the stability of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) receptors and prevents their destruction. This interaction is very important in HER2 (+) breast cancer, as increased HER2 signaling triggers aggressive tumor behavior. HSP70 supports the survival of cancer cells by protecting mutant forms of the tumor suppressor p53 from destruction and thereby increases apoptosis resistance. In addition, it prevents apoptosis by stabilizing anti-apoptotic proteins, such as BCL-2 and B-cell lymphoma-extra large (BCL-XL), thus not only promoting tumor progression but also supporting the formation of resistance to therapeutic treatment. In addition, HSP70 contributes to two fundamental features of cancer cells, namely sustainable cell proliferation and metabolic reprogramming, by stabilizing the Myc oncogene. Thus, it has been shown that the molecular chaperone role of HSP70 is closely related to the regulation of oncogenic pathways and stress responses. In summary, HSP70 stands out as a potential targeted therapeutic agent in cancers where HSP70 is overexpressed or dependent on this chaperone [3, 4].

Apoptotic pathways within breast cancer cells play a critical role in developing therapeutic strategies against tumors [5, 6, 7]. Apoptosis, also known as programmed cell death, is crucial for normal cellular development and tissue homeostasis. Increasing cell death through apoptosis in breast cancer has become a treatment target, making the identification of tumor-specific apoptotic signaling pathways essential for developing more specific therapeutic approaches. Furthermore, cancer stem cells (CSCs) contribute to tumor heterogeneity and therapeutic resistance, showing resistance to conventional chemotherapy and often leading to tumor recurrence [4]. Breast cancer is one of the most common cancer types in women with its heterogeneous structure and different biological subtypes. The molecular differences of these subtypes determine the clinical course of the disease, treatment response, and prognosis. HSP70 as a chaperone protein that plays an important role in the stress response is of central importance in maintaining cellular homeostasis and developing treatment resistance in breast cancer. In addition, its effects on processes, such as CSCs and apoptosis mechanisms, play a key role in regulating tumor formation, metastasis, and response to therapy [4, 8]. This review aims to evaluate the functions of HSP70 in different breast cancer subtypes, its relationships with cancer stem cells, and apoptosis in detail and to evaluate the potential of targeting this molecule in developing new therapeutic approaches.

2. Breast cancer subtypes and HSP70

Types of breast cancers are classified into various subtypes, determined by cell type, growth rate, spread pattern, and prognosis. The most common breast cancer subtypes include invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ. Treatment options vary depending on cancer subtype, growth rate, spread status, and the patient’s health, and they may include surgery, radiation, chemotherapy, hormone therapy, and targeted therapies [9, 10, 11].

Breast cancer subtypes are categorized based on the unique characteristics of cells within the tumor [9, 12, 13, 14]. Breast cancer is commonly characterized by five primary molecular subtypes, often referred to as PAM50 (Prediction Analysis of Microarray 50) subtypes (Table 1).

Due to variations in gene expression and protein levels among these subtypes, the diagnosis and treatment of each breast cancer subtype also differ. Recently, with the advancement of new technologies like single-cell genomics, it has become possible to conduct more detailed molecular classifications of breast cancer. Single-cell genomics is a technology used to examine the genomic structures of individual cells [15, 16, 17]. This approach enables a deeper understanding of genomic diversity and heterogeneity within cancer cells, allowing for the identification of more precise therapeutic targets in cancer treatment [18, 19]. These techniques provide detailed insights into the gene expression profiles of tumor cells, facilitating the identification of more specific subtypes. With single-cell genomics, the genetic characteristics of each cell can be analyzed individually, enabling the identification of differences among distinct cell populations. This advancement aids in a more comprehensive understanding of breast cancer and the development of improved treatment options [9, 13, 20, 21, 22, 23].

HSP70, a member of the heat shock protein (HSP) family, prevents protein misfolding and aggregation under cellular stress conditions. HSP70 plays a critical role in maintaining cellular homeostasis. Cancer cells overproduce HSP70, which enables them to survive under stress conditions. HSP70 is a significant factor in the growth and metastasis of cancer cells. HSP70 belongs to a family of proteins known as heat shock proteins and is expressed in response to cellular stress conditions. Increased expression of HSP70 in breast cancer cells has been observed, suggesting potential links between this protein and breast cancer subtypes. Breast cancer is divided into various subtypes that differ in molecular profile and clinical characteristics (Figure 1).

Investigating the expression of HSP70 across these subtypes and its relationship to cancer progression, invasion potential, and treatment response is essential [24, 25]. The most lethal aspect of breast cancer is its ability to spread to other organs through metastasis. The expression of HSP70 in metastatic breast cancer cells and its role in the metastasis process have yet to be fully elucidated. Particularly, HSP70’s influence on metastasis initiation, apoptosis, cell migration, invasion, and changes in the tumor microenvironment is significant [26, 27, 28, 29]. Resistance to treatments, such as chemotherapy and hormone therapy, is common in breast cancer, and HSP70 expression may be related to these resistance mechanisms. Understanding HSP70’s role in the development of resistance to chemotherapy and hormone therapy could reveal its potential significance in breast cancer treatment [8, 30]. In recent years, immunotherapy has shown promising results in breast cancer treatment. The relationship between HSP70 expression in breast cancer cells and immunotherapy response is especially relevant, as HSP70 might affect mechanisms that modulate immunotherapy efficacy, presenting potential advantages when used in combination with immunotherapy [31, 32, 33]. HSP70 can exhibit anti-apoptotic effects in the apoptosis process by inhibiting apoptotic signaling pathways, preventing cells from entering apoptosis. In addition to these anti-apoptotic effects, HSP70 can also play pro-apoptotic roles by regulating the stability and activity of certain pro-apoptotic proteins, contributing to the apoptosis process. Thus, HSP70 inhibition could induce apoptosis in cancer cells. Many studies have shown that most compounds with anticancer effects show this effect by reducing HSP70 expression and/or HSP70 inhibition [34]. Cancer cells often express higher levels of HSP70 than normal cells, which may help protect them under stress conditions and evade apoptosis. Studies have proposed HSP70 and apoptosis as potential targets for cancer treatment [7, 35, 36]. However, the mechanisms through which HSP70 regulates apoptosis are not yet fully understood and remain an active area of research [37, 38, 39, 40, 41, 42].

HSP70 has been shown to promote tumor cell proliferation and metastasis by regulating Wnt/β-catenin, phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR), and NF-κB signaling pathways in breast cancer [8]. Interestingly, the expressions of HSP70 heat shock proteins are significantly elevated in aggressive basal and triple-negative breast cancer (TNBC) subtypes and genetic downregulation or pharmacological inhibition of the HSP70 resulted in reduced tumor growth and invasion through induction of apoptotic cell death [24, 43, 44, 45].

Furthermore, the heat shock protein family A (Hsp70) member 2 (HSPA2) expression was shown to be higher in Luminal A and B subtypes, while heat shock protein family A (Hsp70) member 5 (HSPA5) and heat shock protein family A (Hsp70) member 6 (HSPA6) expressions were more common in Basal TNBC subtypes. In addition, Zhang and Bi demonstrated that some HSP70 members, such as heat shock protein family A (Hsp70) member 1A (HSPA1A), HSPA5, and heat shock protein family A (Hsp70) member 8 (HSPA8), were significantly increased in breast cancer tissues [46]. Therefore, the varying degrees of HSP70 expressions in breast cancer subtypes may be implicated in aggressive properties of the associated diseases in patients. It may also suggest that HSP70 provides survival advantages under stress conditions and accelerates tumor growth by increasing cell proliferation and suppressing apoptotic pathways as well as increasing therapeutic resistance [24]. In contrast, in hormone-sensitive breast cancers (ER+/PR+), the anti-apoptotic effects of HSP70 are dominant, and it was shown to promote resistance to hormone therapy by increasing tumor cell survival [3, 17].

The heat shock protein 70-2 (HSP70-2) expression was also shown to be highly elevated in breast cancer tumor samples, gradually increasing from ductal situ in carcinoma (DCIS) to invasive ductal carcinoma (IDC) with further increase in higher grades [43]. In this study, silencing of HSP70-2 resulted in a significant decrease in cell growth, motility, and invasiveness due to reversal of epithelial-mesenchymal transition (EMT), while apoptotic cell death is increased. These findings suggest that HSP70-2 may play a critical role in the progression of breast cancer and can be evaluated as a potential therapeutic target [43].

Yamaguchi-Tanaka et al. showed that chemotherapy increases the release of exogenous HSP70 from breast cancer cells, which leads to pro-tumorigenic effects via tumor-associated macrophages (TAMs). It was found that HSP70 release was increased in breast cancer cells treated with epirubicin (EPI), and this has activated TAMs and promoted tumor progression. There was a significant reduction of CD163 + TAMs and reduced expression of transforming growth factor beta (TGF-β) when treated with conditioned medium from HSP70 knockdown MDA-MB231 and MDA-MB453 cells. This study revealed that HSP70 may play a role in the generation of tumor microenvironment (TME) after chemotherapy and can be considered as a factor that promotes tumor growth [47].

Alternative treatment approaches also utilized HSP70 as a promising target for the treatment of breast cancer. Interestingly, onion-derived phytocompounds (e.g., quercetin, cyanidin-3-glucoside, and diosgenin) exhibit strong binding with HSP70 and have better binding scores compared to conventional agents such as Tamoxifen [34]. These findings suggest that herbal compounds can be evaluated as potential agents in the treatment of breast cancer through HSP70 inhibition.

In addition to being a therapeutic target, HSP70 has been utilized as an important biomarker in determining the functional severity of breast cancer type 1 susceptibility protein (BRCA1) mutations. Gracia et al. recently demonstrated that HSP70 preferentially (94%) binds to pathogenic variants of BRCA1, which is the C-terminal region of BRCA1 (BRCT) resulting in the loss of function of breast cancer susceptibility (BRCA) protein [48]. This study also emphasized that hypomorphic variants of BRCA1 maintain partial folding and function by binding moderately to HSP70 but may still predispose to cancer [48].

These findings suggest that HSP70 plays a critical role in the progression of breast cancer and has a significant effect, especially on tumors associated with BRCA1/BRCA2 (breast cancer type 2 susceptibility protein) mutations. Mutated BRCA1 and BRCA2 disrupt DNA repair mechanisms and increase cellular stress response. HSP70 may contribute to the survival of affected cells with accelerating tumor development by playing a protective role against such stress responses. Therefore, the above-mentioned results indicate that HSP70 is not only an indicator of folding disorders but can also function as a prognostic biomarker to determine the risk associated with BRCA1 mutations [48].

In conclusion, HSP70 plays a critical role in the pathogenesis of breast cancer and its effects are multifaceted. HSP70 facilitates cancer progression by increasing the survival of malignant cells and providing protection from chemotherapies as well as evading the immune system. Its association with BRCA1/2, regulation of apoptosis, and contribution to therapy resistance make it an important therapeutic target. Future studies on breast cancer should focus on determining subtype-specific sensitivities to HSP70 inhibition and developing combination therapies.

3. HSP70, cancer stem cells, and apoptosis

Cancer stem cells represent a unique and highly resilient subset of cells within tumors that are believed to drive cancer initiation, progression, and recurrence. CSCs were first identified in acute myeloid leukemia (AML) by Canadian scientist John Dick et al. in 1997, and they have since been found in various cancer types, including breast, colon, and brain cancers [49]. These cells share key characteristics with those of normal stem cells, especially the ability to self-renew and differentiate, allowing them to initiate and sustain tumor growth. This self-renewing capacity, coupled with their resistance to apoptosis, positions CSCs as central players in cancer biology, as they enable tumors to persist and recur even after aggressive treatment. Significant progress in cancer research has revolutionized our understanding of cancer pathogenesis and facilitated the development of innovative therapies that have substantially improved patient outcomes. Despite these advancements, many patients still face challenges, such as treatment resistance, disease recurrence, and metastasis, ultimately leading to disease progression and mortality. Research suggests that a specific subset of cancer cells, known as cancer stem cells, exhibit stem cell-like characteristics, including self-renewal, differentiation, and enhanced proliferative capacity. These stemness traits, regulated by pathways, such as signal transducer and activator of transcription 3 (STAT3), NANOG, NOTCH, WNT, and HEDGEHOG, are often disrupted in CSCs due to genetic and epigenetic alterations. Preclinical studies targeting these stemness pathways, in conjunction with conventional therapies, have shown promising outcomes. As a result, several anti-CSC therapies are currently being evaluated in clinical trials across different stages of development. HSP70 has been shown to inhibit the apoptotic pathways at different levels (Figure 2) [2, 50, 51].

The significance of CSCs in cancer therapy has grown due to their unique ability to evade apoptosis, thereby enhancing their survival, promoting metastasis, and contributing to tumor relapse. Unlike most tumor cells, CSCs are highly adept at withstanding the effects of conventional treatments like chemotherapy and radiotherapy, as they can effectively suppress apoptotic pathways. For example, in cancers such as breast cancer and glioblastoma, CSCs have been shown to drive tumor recurrence and distant metastasis [51, 52]. A key molecule implicated in the survival of CSCs is HSP70, a chaperone protein involved in cellular defense mechanisms under stress. HSP70 is highly expressed in many cancer types and exerts a strong anti-apoptotic effect, particularly in CSC populations [51, 52]. This anti-apoptotic property of HSP70 allows CSCs to avoid treatment-induced cell death and maintain their stem cell-like qualities, even under intense therapeutic stress. By preventing apoptosis, Hsp70 enables CSCs to resist traditional therapies and contributes to treatment resistance [52]. The interplay between CSCs, HSP70, and apoptosis suppression has spurred interest in developing targeted therapies that disrupt these protective mechanisms. Research increasingly focuses on understanding the molecular pathways through which Hsp70 promotes CSC survival and apoptosis evasion [3]. By elucidating Hsp70’s role within the tumor microenvironment and its influence on CSC biology, researchers aim to identify new therapeutic strategies that weaken CSC defenses, improve treatment efficacy, and reduce cancer recurrence. Targeting the interactions between CSCs, HSP70, and apoptotic pathways could represent a promising approach in developing more effective cancer therapies [53, 54]. Cancer stem cells are cells with the capacity for self-renewal and differentiation, closely linked to the initiation, progression, and recurrence of tumors (Figure 2). These cells can resist conventional therapies, potentially leading to tumor recurrence. CSCs are preserved within specialized niches in the tumor microenvironment and may be the main source of relapse after treatment. Proteins such as HSP70 play a role in maintaining and enabling resistance mechanisms in CSCs, and inhibiting these proteins could lead to more effective therapeutic strategies targeting CSCs [55].

Apoptosis, or programmed cell death, is critical in maintaining cellular homeostasis [55, 56]. Cancer cells survive by suppressing apoptotic mechanisms, and CSCs may have even more resistance to apoptosis. Proteins like HSP70 can interact with apoptosis-regulating proteins, preventing cell death. Inhibiting these proteins could reactivate apoptosis, potentially killing cancer cells. The inhibition of HSP70 offers promising strategies for effective therapies against CSCs. Future research aims to improve understanding and targeting of these proteins. Clinical trials are testing treatments targeting HSP70, which may pave the way for breakthroughs in CSC therapy [4]. Although targeting these proteins presents challenges, developing inhibitors may play a significant role in overcoming treatment resistance. Future studies should focus on understanding the molecular mechanisms of HSP70 in greater depth to develop new therapeutic strategies. HSP70 supports the resistance mechanism of CSCs, suppresses apoptosis, and increases treatment resistance in different breast cancer subtypes (Figure 3). HSP70 inhibits caspase activation by BCL-2 and since this pathway is stronger in CSCs, treatment efficacy decreases. In addition, Hsp70 promotes proliferation by supporting HER2 signaling [56, 57, 58, 59]. It can cause resistance to immunotherapy by making CSC phenotypes resistant, especially in the TNBC subtype. Hsp70 has also been shown to play a role in resistance to hormonal treatment in luminal subtypes [60, 61].

Research has explored the effects of HSP70 on apoptotic signaling pathways, cellular mechanisms, and the molecular regulation of apoptosis. One member of the HSP70 family, heat shock protein 90 (HSP90), is known to regulate intracellular signaling pathways in cancer cells, influencing cell growth, proliferation, and resistance to apoptosis [62, 63]. Beere et al. identified a mechanism by which HSP70 inhibits apoptosis by preventing the addition of procaspase-9 to the Apaf-1 (apoptotic protease-activating factor 1) apoptosome [64]. Additionally, Bagatell and Whitesell explored HSP90 inhibition as a therapeutic target, finding that it induced apoptosis in breast cancer and other cancer types, which suggests HSP90 inhibition may affect apoptosis through HSP70 interactions [65]. HSP70 has also been implicated in regulating immune cells’ attack on cancer cells, contributing to the immune system’s destruction of cancer cells. Calderwood and Neckers noted that HSP70 and HSP90 interaction plays a regulatory role in apoptosis within cancer cells and that HSP70 inhibition could increase apoptosis in breast cancer cells [62]. In a meta-analysis by Dimes et al., high HSP70 expression levels were associated with breast cancer progression, potentially affecting prognosis [66]. Furthermore, Du et al. reported that HSP70 inhibition enhances tumor cell sensitivity to radiotherapy by promoting apoptosis through interfering with mitochondrial integrity, blocking apoptotic complex formation, and impairing DNA damage repair mechanisms [67]. Anadon et al. tested a novel small molecule inhibitor, 2-phenylethynesulfonamide (PES), and found that targeting HSP70 with PES induced apoptosis in ovarian cancer cells, suggesting a potential treatment strategy [68]. Studies highlight that members of the HSP70 family promote cancer cell growth through various mechanisms and that HSP70 inhibitors might be promising therapeutic targets in breast cancer, with potential pro- and anti-apoptotic effects [69, 70, 71, 72].

As mentioned above, Hsp70 is one of the molecules in the heat shock protein family, playing a critical role in cellular stress response while regulating correct protein folding and intracellular protein homeostasis. However, the relationship between apoptosis and HSP70 is not yet fully understood, and further research is needed. Detailed studies examining their molecular mechanisms and potential interactions will help us better understand the relationship between apoptosis and HSP70 and potentially aid in the development of new therapeutic strategies. HSP70 plays a dual role in CSCs and apoptosis, which are critical to breast cancer development and treatment resistance. HSP70 interacts with CSC-associated pathways, such as Wnt/β-catenin and NOTCH1, to promote stemness, self-renewal, and tumorigenic potential. These interactions contribute to tumor initiation, metastasis, and treatment resistance. HSP70 prevents apoptosis by stabilizing anti-apoptotic proteins, such as BCL2 and impairing caspase activation. In TP53 mutant cancers, HSP70 also promotes survival by preventing the degradation of dysfunctional p53 protein (Figure 4).

Today, the role of HSP70 in the apoptosis process is increasingly emphasized in in vitro studies using breast cancer cell line models, with a focus on their expression levels, localization, interactions, functions, and molecular mechanisms. The expression levels of HSP70 in breast cancer cells are evaluated concerning different treatment responses across various breast cancer subtypes. At the same time, intensive research is conducted on topics, such as HSP70 in breast cancer cells, modulation of intracellular signaling pathways, and apoptosis processes. Research on HSP70 in breast cancer cell line models today helps us understand their molecular mechanisms, potential interactions, and cellular functions in more detail. These studies provide valuable insights into breast cancer pathophysiology, treatment strategies, and the development of targeted therapies [3, 41, 66, 73]. Additionally, gene expression analyses conducted to examine the expression level changes of HSP70 in breast cancer cells shed light on how HSP70 gene expression varies in different breast cancer cell lines, treatment conditions, or clinical samples. A study by Mhaidat et al. focused on the protective effect of HSP70 against apoptosis induced by 5-fluorouracil (5-FU) in colorectal cancer cells. It was found that HSP70 reduces cell apoptosis induced by 5-FU by inhibiting the activity of Bcl-2-associated X protein (Bax), an apoptotic protein [74]. Another study investigated the effects of HSP70 inhibition on inducing apoptosis and inhibiting tumor growth in hepatocellular carcinoma [75]. They found that Hsp70 inhibition increases apoptosis and suppresses tumor growth in hepatocellular carcinoma cells, suggesting that HSP70 inhibitors could serve as a potential therapeutic strategy in cancer types like hepatocellular carcinoma. On the other hand, HSP70 is a chaperone protein synthesized in response to cellular stress conditions, helping cells cope with stress. HSP70 has also been shown to play an important role in processes, such as protein folding, cellular homeostasis, and apoptosis [73, 76].

Recent research has shown that single-cell genomics technology can also be used in breast cancer research. With single-cell genomics, it is possible to gain a better understanding of genomic differences and heterogeneity in breast cancer cells, classify cancer cells more effectively, and identify targets in cancer treatment. Studies using single-cell genomics technology aim to better understand genetic heterogeneity and various subtypes of cancer cells in breast cancer. In these studies, the genomes of cancer cells from patient samples were individually examined, and genomic characteristics of different subtypes of cancer cells were identified. Moreover, single-cell genomics technology enables better identification of breast cancer subtypes, more accurate diagnosis of the disease, and the development of treatment methods.

4. Therapeutic use and potential of HSP70 inhibitors

Considering the roles of HSP70 in suppressing apoptosis, promoting tumor progression, and providing resistance to chemotherapy, inhibitors targeting HSP70 are thought to be an important therapeutic tool in cancer treatment. We have previously mentioned that breast cancer is a complex disease with a heterogeneous structure and different biological subtypes. In breast cancer subtypes, overexpression of HSP70 is associated with suppression of apoptosis and resistance to treatment. Therefore, inhibitors targeting HSP70 stand out as a promising therapeutic strategy, especially in aggressive subtypes. TNBC is one of the breast cancer subtypes with one of the highest expression levels of HSP70. HSP70 suppresses apoptotic signals by stabilizing TP53 mutations and increases cancer stem cell-like properties. It is suggested that HSP70 inhibitors can be used to both activate apoptotic signals and increase sensitivity to chemotherapy in TNBC cells. In HER2 (+) tumors, HSP70 supports the overactivation of the HER2 receptor by increasing its stability. This may lead to accelerated cell proliferation and resistance to anti-HER2 treatments. HSP70 inhibitors may create a synergistic effect when combined with anti-HER2 treatments by disrupting HER2 stability and targeting this signaling pathway. In Luminal A and B subtypes, HSP70 supports cellular growth by keeping hormone receptors stable. It is suggested that HSP70 inhibitors can be used in these subtypes, especially in patients who have developed resistance to endocrine treatments. Combination treatments have a strategic importance to increase the effectiveness of HSP70 inhibitors in breast cancer. When combined with standard chemotherapeutic drugs, such as Doxorubicin or Paclitaxel, HSP70 inhibitors make tumor cells more susceptible to apoptosis. HSP70 inhibitors can also be effective in treatment-resistant tumors when used with targeted drugs, such as Trastuzumab (HER2+), Everolimus (mTOR inhibitor), or Palbociclib (cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor). The clinical use of HSP70 inhibitors requires the development of more specific and selective agents to minimize side effects in healthy tissues. Nanoparticle systems that will deliver HSP70 inhibitors directly to breast tumors will increase therapeutic efficacy while reducing side effects. It is thought that determining patient groups using HSP70 expression levels and subtype-specific biomarkers will increase the success of these treatments [3, 4, 9, 17, 45, 46, 77, 78, 79].

5. Conclusion

In summary, HSP70 stands out as a critical molecule in the complex landscape of cellular stress responses, apoptosis, and breast cancer. As a chaperone protein that helps maintain cellular stability under stress, HSP70 plays an important role in supporting cell survival, especially in cancer cells exposed to therapeutic stressors. In the context of breast cancer, the anti-apoptotic properties of HSP70 are particularly important because they help protect cancer cells from the effects of chemotherapy, thereby contributing to treatment resistance. HSP70 inhibitors are emerging as a powerful therapeutic key, especially in aggressive and treatment-resistant breast cancer subtypes. Preclinical and clinical studies suggest that these inhibitors may be effective both as monotherapy and in combination therapies. However, further research is needed to optimize these strategies and transition them to clinical use. Emerging research highlights the connection between HSP70 and CSCs, which are implicated in tumor initiation, metastasis, and recurrence. CSCs possess unique mechanisms to survive and proliferate under adverse conditions, including an enhanced resistance to apoptosis. HSP70 may support CSCs by stabilizing their cellular machinery, thus preserving their “stemness” and resistance to treatments. This interaction suggests that HSP70 not only aids cancer cells in evading apoptosis but may also play a role in the persistence and resilience of CSC populations, which are often challenging targets in conventional therapies. Further investigation into the specific roles of HSP70 in CSCs and breast cancer subtypes can help elucidate the molecular pathways that underlie apoptosis evasion and therapeutic resistance. Insights gained from these studies could aid in developing innovative strategies targeting HSP70 to reduce CSC survival and overcome treatment barriers. By exploring HSP70’s functions across different molecular profiles within the breast cancer microenvironment, we may open new avenues for personalized treatments aimed at effectively targeting CSCs and reducing recurrence.

Acknowledgments

This study was supported by the Scientific and Technological Research Council of Turkey (TUBITAK) under the 2219-International Postdoctoral Research Fellowship Program (Project no: 1059B192301226). This study was supported by the National Institute of Health NCI grant R01CA251676 and Karmanos Cancer Institute Startup fund to H. Korkaya.