Lipocalin-2 for Targeted Cancer Therapy

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1		Benoit Stijlemans	--	4049	2023-10-31 12:47:59	\|
2	format change	Peter Tang	-1 word(s)	4048	2023-11-01 01:40:24	\|

This entry is adapted from the peer-reviewed paper 10.3390/cancers15215159

Within the tumor microenvironment (TME) exists a complex signaling network between cancer cells and stromal cells, which determines the fate of tumor progression. Hence, interfering with this signaling network forms the basis for cancer therapy. Yet, many types of cancer, in particular, solid tumors, are refractory to the used treatments, so there is an urgent need for novel molecular targets that could improve anti-cancer therapeutic strategies. Lipocalin-2 (Lcn-2), a secreted siderophore-binding glycoprotein that regulates iron homeostasis, is highly upregulated in various cancer types. Due to its pleiotropic role in the crosstalk between cancer cells and stromal cells, favoring tumor progression, it could be considered as a novel biomarker for prognostic and therapeutic purposes.

lipocalin-2 iron transport tumor-associated macrophages cancer cell death

1. Introduction

In the past 20 years, cancer research has expanded and diversified enormously, whereby specifics and different manifestations of the disease have been investigated using high-throughput technologies, as well as computational and experimental tools, creating huge amounts of data, also referred to as “big data” on cancer research ^[1]. Based on these data, Hanahan and Weinberg, at the beginning of the 21st century, defined the hallmarks of cancer as a tool to identify the capabilities that normal human cells acquire on their way to becoming malignant cells ^[2]. The list of hallmarks of cancer expanded by an additional two by the year 2011, and a recent publication by Hanahan incorporated another four, bringing the total number to fourteen hallmarks of cancer ^[3]^[4].

Reprogramming or dysregulating cellular metabolism is one of the key elements of the hallmarks of cancer and is an essential aspect that tumor cells acquire to support accelerated cell proliferation and to allow for the maintenance of their enhanced biological functions. In this context, it was shown that glucose metabolism is one of the main dysregulated metabolic pathways that also leads to the dysregulation of protein and gene expression and, consequently, tumorigenesis, whereby cancer cells rely on aerobic glycolysis ^[3]^[5]. The uncontrolled proliferation of neoplastic cells is also dependent on the dysregulation of multiple other nutrients besides glucose, with iron being key to the maintenance of the cancer cells’ high metabolic demand ^[6]^[7]^[8]. Hence, alterations in iron metabolism are considered drivers of cancer cells’ aggressive behavior, including their uncontrolled proliferation, resistance to apoptosis, and enhanced metastatic ability. Moreover, dysregulated iron homeostasis has been associated with the development of an adverse tumor microenvironment (TME). In this context, macrophages, among other functions, play a very essential role in maintaining iron homeostasis, as they recycle, store, and release the iron into their surroundings. Within the TME, tumor-associated macrophages (TAMs), especially M2-like cells, contribute to cancer cell survival, promotion, and metastasis ^[9]^[10]. Previous studies showed that the iron-releasing phenotype is one of the defining characteristics of these M2-like macrophages, whereby Lipocalin-2 (Lcn-2) serves as a carrier protein ^[11]^[12]. Lcn-2, also known as neutrophil gelatinase-associated lipocalin (NGAL), oncogene 24p3, siderocalin, or uterocalin, is a 25 kDa glycoprotein that was initially discovered as part of the innate immune system, but was later discovered to deliver iron to the fast-growing tumor cells within the TME ^[13]^[14]. Macrophage polarization is closely associated with the differential regulation of iron metabolism, whereby an increase in TAM’s Lcn-2 expression causes an iron release phenotype that supports tumor growth and therapy resistance ^[15]^[16]^[17].

Another hallmark of cancer in which Lcn-2 could play a role focuses on the apoptotic resistance of cancer cells. Cancer cells are capable of circumventing apoptosis by, for example, losing the function of tumor suppressor genes such as tumor protein 53 (TP53), by downregulating proapoptotic factors such as Bim, Bax, and Puma, by increasing the expression of survival signals such as insulin-like growth factor 1 and 2 (Igf1/2), or by upregulating antiapoptotic proteins such as Bcl-x_L and Bcl-2 ^[3]. Moreover, the deprivation of trophic factors, such as IL-3, can also lead to apoptosis, whereby Lcn-2, being transcriptionally regulated by IL-3 deprivation, induces apoptosis ^[18]^[19]. Additionally, Lcn-2, being an alternative regulator of iron homeostasis, was also shown to play a role in an iron-dependent, non-apoptotic mode of cell death called ferroptosis, which is characterized by alterations in intracellular iron levels and lipid peroxidation ^[20]. Important to mention is that ferroptosis is driven by disordered iron metabolism, resulting in the production of reactive oxygen species that induce the Fenton reaction and/or impair mitochondrial iron metabolism ^[21]. The upregulation of iron transport due to inflammation can cause lipid accumulation and oxidative stress, which is further fueled by Lcn-2′s ability to internalize iron ^[22].

High expression of Lcn-2 in cancerous tissues of the thyroid, ovarian, breast, prostate, pancreatic, renal, and colorectal organs underline the tumor-promoting role of Lcn-2. This is attributed to the fact that Lcn-2 is also able to promote epithelial-to-mesenchymal transition (EMT) and bind to matrix metalloprotease 9 (MMP9), thereby modulating the metastatic phenotype of cancer cells. In addition, Lcn-2 was shown to contribute to the polarization of macrophages and, in turn, to promote iron delivery to cancer cells, whereby the increase in intracellular iron protects cancer cells from apoptosis ^[23]^[24]^[25]^[26].

2. Role of Iron in Cancer Progression

Iron is involved in many important functions in mammalian cells, such as cell metabolism, proliferation, and growth ^[6]. More than half of the total amount of iron is stored in erythrocytes as part of hemoglobin, providing oxygen transport throughout the body. Besides this, it is also used as a helper molecule for an array of proteins, playing a key role in cell cycle progression, DNA synthesis and stability, oxidative phosphorylation, and the citric acid cycle ^[6]. Due to the low availability of iron in circulation, proteins involved in the import, storage, and export of iron need to be highly regulated. Although iron plays an essential role as a cofactor for enzymes, due to its ability to lose and gain electrons, it can also be potentially dangerous as it can play a role in free-radical reactions, which can be mutagenic ^[27]^[28]. One of these reactions is the Fenton reaction, whereby ferrous iron (Fe²⁺) donates an electron to hydrogen peroxide, making a hydroxyl radical, which is an oxidant of reactive oxygen species (ROS). ROS can induce lipid and protein modifications in cancer cells, leading to aggressiveness and metastasis. Conversely, the accumulation of iron-dependent lipid modifications can lead to ferroptosis (i.e., iron-dependent cell death), which will have a tumor-suppressing role ^[29]^[30]. Hence, iron-regulation plays a pivotal role in cancer by exerting both tumor-promoting functions and tumor-suppressing functions. In addition, a lack of iron can cause anemia, which, in turn, has a tumor-promoting effect by causing hypoxia that fuels M2 polarization ^[31]. In this context, the occurrence of cancer-related anemia (CRA) is one of the most frequent secondary problems and is linked to disease progression (i.e., the occurrence of metastasis) as well as the tumor site and age of the patient ^[32]. In fact, CRA is a cytokine-mediated disorder resulting from complex interactions between tumor cells and the immune system and is characterized by biological and hematologic features that resemble those described in anemia associated with chronic inflammatory disease (i.e., anemia of inflammation) ^[33]. It was also shown that the release of certain inflammatory cytokines during anemia of inflammation negatively affects erythroid progenitor cell differentiation. In this context, tumor cells can produce cytokines that negatively affect erythroid progenitor cell differentiation. Moreover, Lcn-2 has been shown to also affect erythropoiesis negatively, and this is related to the occurrence of hypoxic TAMs and the development of metastasis ^[34]^[35]^[36]. Hence, Lcn-2, through its iron-regulating role, could be implicated as a pivotal player in CRA by regulating the inflammatory immune response within the TME and iron availability for erythropoiesis ^[37]^[38]^[39]. While carcinogenesis is known to cause a decrease in the production of red blood cells, the main cause of anemia during cancer is a consequence of radio- or chemotherapy, which are immunosuppressive and often damage erythroid progenitors and/or reduce erythrocyte half-life ^[40].

Dysregulated iron homeostasis is associated with the malignant cancer phenotype, whereby the change in the expression of iron-regulating genes promotes higher metabolic needs of cancer cells ^[41]. The key players in iron homeostasis are (i) transferrin (Tf), which is the main iron transporter that, upon binding to the transferrin receptor 1 (TfR1), allows for iron import; (ii) heme oxygenase 1 (Hmox1), which plays a key role in iron regulation and ROS production; (iii) divalent metal transporter 1 (DMT1), which allows for intracellular iron transport from the endosome to the cytosol; (iv) ferritin (FT), which is essential for iron storage; and (v) ferroportin (FPN), which is the sole iron exporter regulated by hepcidin ^[42]^[43]^[44]^[45]. TfR1, FT, DMT1, Hmox1, and hepcidin levels are highly upregulated in breast, prostate, lung, and squamous cell carcinoma, while FPN levels are significantly lowered compared to those in healthy tissue ^[46]^[47]^[48]. Simultaneously, iron is highly internalized and stored by cancer cells, while its efflux is halted by the dysregulation of FPN expression ^[48]. Furthermore, changes in iron levels also regulate a multitude of tumor-suppressive signaling pathways, such as those related to tumor protein 53 (p53), c-myc, nuclear factor erythroid 2-related factor 2 (NRF2), Harvey rat sarcoma virus (H-RAS), signal transducer and activator of transcription (STAT3), extracellular signal-regulated kinase ½ (ERK1/2), protein kinase B (AKT), and hypoxia-inducible factors 1α and 2α (HIF1α and HIF2α) ^[7]. Overall, it is clear that cancer cells demand a higher uptake of iron, which cannot be mediated solely via the Tf-TfR-mediated pathway. Therefore, Lcn-2, a transferrin-independent iron carrier, allows cancer cells to acquire the additional necessary iron. This process of non-transferrin-mediated iron uptake, involving Lcn-2 as a key player, has been shown to be involved in cancer progression ^[49]. However, Lcn-2 is unable to bind to iron directly, but it can bind to the iron–siderophore, or siderophore-like, complex, and can be internalized by the high-affinity cell surface receptor SLC22A17 (24p3R) ^[50].

Bauer et al. assessed Lcn-2 expression in a representative cohort of 207 breast cancer patients, whereby a strong association was found between Lcn-2 expression and prognostic factors such as the Ki-67 proliferation index, lymph node involvement, and human epidermal growth factor receptor 2 (HER-2/neu) status and histological grade ^[51]. Although there is no correlation between Lcn-2 and spontaneous polyoma-middle-T oncogene (PyMT) breast cancer parameters, Mertens and colleagues reported a positive relationship between the expression of Lcn-2 and tumor onset, lung metastases, and recurrence. This was mediated by stromal cells, mainly macrophages, whereby Lcn-2^−/− TAMs stored more iron compared to wild-type TAMs ^[17]^[52]. A study by Tymoszuk and colleagues showed a negative influence on the efficacy of different immunotherapies after iron administration. Indeed, supplementing E0771 triple-negative breast cancer-bearing mice with isomaltoside, an iron compound typically used for the treatment of patients with iron deficiency (linked to anemia), promoted tumor growth by negatively impacting T-cell-mediated immune function and infiltration, also impairing the efficacy of anti-PD-L1 and IL-2/doxorubicin immunotherapies ^[53]. Conversely, iron-chelating therapies (e.g., deferoxamine, DFO) were shown to decrease cancer cell growth in a leptomeningeal metastasis model. It was shown that macrophages provide signals that trigger Lcn-2 production by cancer cells, which, in turn, allows cancer cells to outcompete macrophages in acquiring iron by using Lcn-2 as alternative iron supply. Yet, DFO treatment was shown to impair the tumor growth and shRNA of Lcn-2, and its receptor was shown to impair the iron acquisition and proliferation of tumor cells ^[54]. A relationship between clear-cell renal cell carcinoma (ccRCC) and Lcn-2 in the context of iron regulation was studied by Rehwald et al., which provided new insights into the contribution of iron-loaded Lcn-2 in matrix adhesion and migration. It was shown that patients suffering from ccRCC have an elevated level of the iron-loaded form of Lcn-2. By stimulating human patient-derived tumor cells (T-TEC) in vitro with a mutant, non-iron-binding Lcn-2, the iron-binding capacity was disabled in comparison to normal non-modified protein, resulting in a significant reduction in the intracellular iron amount. Importantly, adhesion to collagen I or fibronectin matrices, which are crucial for cancer cell migration and matrix adhesion, were inhibited using non-iron-binding Lcn-2 ^[55].

Finally, previous years focused on targeting the iron regulation mechanism as a potential anticancer therapy. This is true for both iron chelator-based therapies, such as the already mentioned DFO, deferasirox (DFX), ciclopiroxolamine (CPX), Vlx600, Dpc, and thiosemicarbazone, as well as for iron trafficking-based therapies such as the targeting of hepcidin, FPN, and TfR1 ^[42]^[56]. The former strategies lead to a lot of side effects due to poor cancer cell targeting in the TME, whereby a lot of nonmalignant cells are affected, leading to strong cytotoxicity. The latter faced ambiguous results. Some promising results were obtained by targeting the hepcidin/IL-6 axis, or the hepcidin/IL-8 axis, leading to decreased metastasis of breast cancer to the liver, lymph nodes, and lungs, while anti-TfR antibodies were only effective in some patients and in certain cancer subtypes, whereby anemia was reported as an important side-effect ^[57]^[58]^[59]. However, recent improvements and optimization for targeting the Tf-TfR system are still considered promising, especially in multidrug-resistant tumor cells ^[60]. Nevertheless, as previously indicated, cancer cells can go beyond the classical iron uptake pathway to allow for iron scavenging from the surroundings. Hereto, the Lcn-2/Lcn-2R pathway could be an interesting target, whereby blocking of the iron-binding region or receptor-binding region of Lcn-2 would lead to reduced iron availability in the TME.

3. Lipocalin-2 in Cancer Progression

The involvement of Lcn-2 in carcinogenesis has been studied using murine models, in human and murine cancer cell lines, and in patients. One of the malignancies in which Lcn-2 has been most studied is breast cancer, where the increased expression of Lcn-2 in carcinoma tissue, urine, and sera correlates with a poor prognosis and increased aggressiveness. The study conducted by Provatopoulou revealed that Lcn-2 plays a heterologous role in the development of breast carcinoma. It was shown that Lcn-2 serum levels did not differ in women with benign breast conditions that might lead to breast cancer, such as atypical ductal hyperplasia, ductal carcinoma, and sclerosing adenosis, compared to healthy controls. However, there was a significant increase in Lcn-2 expression in patients with invasive ductal carcinoma (IDC), which is the most common type of invasive breast cancer, whereby a significant positive association was found between the disease severity score and Lcn-2 expression in serum ^[61]. Compared to other breast carcinomas, triple-negative breast cancer (TNBC) has more aggressive tumor progression and worse prognosis, whereby the metastasis of this cancer subtype leads to a 5-year survival rate of only 10.8% ^[62]. It was found that Lcn-2 expression can be considered an independent prognostic biomarker for the reduced survival of breast cancer patients, particularly those suffering from TNBC. Of note, for the more rare but most aggressive and deadly variant of primary breast cancer, i.e., inflammatory breast cancer (IBC), high levels of Lcn-2 have also been associated with a poor prognosis and reduced overall survival. A relationship between other markers of poor breast carcinoma prognosis, such as progesterone receptor (PR)- and estrogen receptor (ER)-negative status and Lcn-2, has been reported in primary breast carcinoma. However, heterogenous expression of Lcn-2 at protein and mRNA levels was also described by Stoesz, whereby Lcn-2 was detected in 42.2% of patients ^[63]^[64]. Furthermore, patients in stages II and III were reported to have increased expression of Lcn-2 in the tumor stroma, compared to healthy tissue, and patients with metastatic breast cancer were reported to have increased expression of Lcn-2 in the urine ^[65]. Guo and colleagues showed that the siRNA silencing of Lcn-2 in a TNBC model inhibited angiogenesis in vivo and in vitro, while in a similar study on IBC, the depletion of Lcn-2 in cell cultures reduced invasion, migration, and the cancer stem cell population ^[66]^[67]. Furthermore, secreted factors by four stromal components (fibroblasts, lymphatic endothelial cells, macrophages, and blood microvascular endothelial cells) were screened upon stimulation with conditioned medium from four different TNBC cell lines (MDA-MB-231, SUM159, MDA-MB-468, and SUM149). The results showed that Lcn-2, together with IL-6, CCL5, and IL-8, was significantly upregulated in the crosstalk between four different TNBC cell lines and stromal cells ^[68]. Finally, core biopsies of 652 breast cancer patients undergoing neoadjuvant chemotherapy, examined via immunohistochemistry, revealed that the intensity and expression of Lcn-2 were significantly related to estrogen and progesterone receptor status, as well as with the histological tumor type ^[64].

Lcn-2 was also found to be upregulated in residual cancer cells, found in the host after chemotherapeutic treatment that causes senescence of cancer cells. These senescent cells release a set of pro-inflammatory chemokines, cytokines, and growth factors, which collectively are referred to as the senescence-associated secretory phenotype (SASP). Additionally, the inactivation of Lcn-2 by CRISPR/Cas9 gene deletion increases the response to chemotherapy in murine breast cancer. Importantly, it was shown that neoadjuvant therapy leads to the upregulation of Lcn-2 in human breast tumors, highlighting the importance of targeting Lcn-2 as an additional therapeutic approach ^[69]. Studies on murine and human cancer cells revealed a correlation between breast carcinoma progression and Lcn-2 expression. For instance, using the well-established polyomavirus middle T antigen (MMTV-PyMT) breast carcinoma model, it was shown that crossing MMTV-PyMT mice with Lcn-2^−/− mice resulted in a decreased tumor onset and burden compared to wild-type MMTV-PyMT mice. Interestingly, discoveries using experimental mouse and human cell lines correlate with findings in patients ^[70]^[71]^[72].

Also, in other cancer types, Lcn-2 was reported to promote tumor progression. The expression level of Lcn-2 in the bile of cholangiocarcinoma (CCA) patients was significantly higher than in control groups, while Lcn-2 knock-down inhibited cell growth in vitro and in vivo, while the overexpression of Lcn-2 increased the cell metastatic potential, making it overall a potentially prognostic marker for this disease ^[73]. Lcn-2 was also identified as an important suppressor of radiotherapy success in oral squamous cell carcinoma (OSCC), whereby radiated Ca9-22 cells showed the strongest increase in Lcn-2 expression. The radiosensitivity was also increased in lung carcinoma upon Lcn-2 knock-down by siRNA ^[16]. A mouse model of hepatoblastoma (HB) was reported to have high expression levels of Lcn-2, with the highest rate in its embryonal form. In most human HB samples, Lcn-2 is highly expressed, and there is a correlation between Lcn-2’s presence and the histological subtype within individual tumors. Whilst there are some conflicting data on the role of Lcn-2 and its inhibition of epithelial-to-mesenchymal transition (EMT) in hepatocellular carcinoma, Molina et al. suggested that hepatocyte-derived Lcn-2 could serve as a potential serum biomarker in HB ^[74].

Overall, numerous studies have shown that Lcn-2 facilitates tumorigenesis by enhancing tumor cell growth and survival, and by increasing cellular resistance to chemotherapeutics and iron-induced toxicity ^[16]^[75]. Mechanistically, the oncogenic role of Lcn-2 is associated with its ability to make a complex with MMP9. The overexpression of Lcn-2 and MMP9 is associated with an early promoter methylation status, leading to the development of primary tumors ^[76]. Other studies proposed that the contribution to tumor metastasis is attributed to Lcn-2′s ability to promote EMT, which is a central process in cancer cell dissemination ^[24]^[77].

However, recent studies showed that Lcn-2 can have both a pro- and anti-tumorigenic role depending on the tumor stage, type, and location. This opposing role of Lcn-2 appears to be regulated in an iron-dependent manner, whereby holo-Lcn-2 (i.e., iron–siderophore-loaded Lcn-2), can fuel tumor growth, while apo-Lcn-2 (i.e., iron–siderophore-complex-free Lcn-2), promotes apoptosis. Tong et al. showed that Lcn-2 overexpression significantly blocked pancreatic cancer cell invasion and adhesion and potently decreased angiogenesis in vitro, yet it did not affect cancer cell viability and survival ^[78]. Also, Lcn-2 expression substantially inhibited liver metastasis upon inoculation of nude BALB/c mice with a human highly metastatic liver cancer cell line, KM12SM, thereby proving that Lcn-2 can also have a negative effect on tumor development ^[79]. However, the literature on the tumor-suppressive function of Lcn-2 is limited, and less frequently reported ^[80].

4. Cell Death and Lipocalin-2

One of the mechanisms contributing to drug resistance and treatment failure in cancer cells is their ability to alter cell death pathways. The homeostasis of an organism is, among various mechanisms, dependent on the dynamic production and elimination of cells. Though many forms of cell death exist, the best characterized form is apoptosis, which was shown to mediate tumor regression following chemo/radiotherapy ^[81]. Uncontrolled tumor cell initiation and proliferation, which are some of the main phenotypes of malignant cells, could be led by the inactivation of pro-apoptotic proteins or the expression of anti-apoptotic factors, which was reported by different groups ^[82]. On the other hand, the modulation of ferroptosis, a form of cell death related to iron availability in the cell, also resulted in inhibition of the migration and proliferation of cells ^[83]^[84]. Intriguingly, Lcn-2 was reported to be involved in both apoptotic and ferroptotic mechanisms, whereby a central player is iron and its distribution within the cell and the TME.

5. Lipocalin-2 as a Potential Therapeutic Target

Although Lcn-2 is shown to be highly expressed in certain carcinomas, using Lcn-2 as a therapeutic target has only been tried in the early stages of tumor development. Some of the current strategies to target Lcn-2 involve (i) gene editing techniques, (ii) protein regulation by using antibodies and small-molecule inhibitors, (iii) targeting Lcn-2-related pathways, and (iv) post-transcriptional regulation through RNA interference.

The relationship between TNBC and Lcn-2 was studied, whereby a tumor-targeted nanolipogel (tNLG) successfully knocked out Lcn-2 via the CRISPR technique from human TNBC cells, leading to a significant decrease in TNBC aggressiveness via modulation of epithelial-to-mesenchymal transition and migration, which resulted in an overall smaller tumor growth ^[85].

Anti-Lcn-2 antibodies have been developed in the last two decades, with the main focus on the destabilization of the Lcn-2/MMP9 complex. Leng and colleagues based their study on a spontaneous mouse breast cancer model (using transgenic mice carrying the mutant form of ErbB2(V664E) driven by the mammary-specific promoter MMTV), in which they observed significantly delayed lung metastasis, and lowered MMP9 expression and activity, in Lcn-2-deficient mice. Next, they expanded their study by using polyclonal anti-Lcn-2 antibodies in an aggressive mouse 4T1-induced mammary tumor model and showed strong interreference with lung metastasis, yet almost no effect on the primary tumor growth ^[86]. This could be due to the size of the antibody that prevents achieving a sufficiently high concentration within the TME. Although iron chelators and anti-MMP9 moieties have continued to be studied separately, there is a need to further evaluate anti-Lcn-2 antibodies in clinical trials, and in combination with current therapies for specific cancer subtypes.

Targeting Lcn-2-related pathways focuses mainly on breast carcinoma studies. In this context, the downregulation of the NFAT3 transcription factor involved in the anti-invasive and anti-migratory phenotype of breast cancer was found to result in a threefold increase in Lcn-2 expression. This increased expression of Lcn-2 further upregulated the invasion and migration capacity of different estrogen receptor α (ERA+) breast cancer cells, such as BT-474, MCF-7, ZR-75-1, and T-47D. Although the addition of recombinant Lcn-2 to ERA+ cells was sufficient to rescue the inhibition of migration elicited by NFAT3, it did not affect NFAT3′s actin reorganization, which could imply a different migration-regulating mechanism targeted by Lcn-2 ^[87]. Interestingly, one study by Gwira et al. suggests that Lcn-2 can trigger the activation of the ERK pathway, but this needs to be investigated in depth ^[88]. Another group studied the effect of the inhibition of the Lcn-2-targeted pathway using ER-negative (ER-) breast cancer and revealed that the transcription factor CCAAT enhancer-binding protein ζ (C/EBP ζ) plays a role in Lcn-2 expression. Indeed, the overexpression of C/EBP ζ in MDA-MB-231 cells resulted in decreased MMP9 and Lcn-2 expression, coinciding with the inhibition of the migration and invasion of breast cancer. Also, C/EBP ζ was found to directly repress human Lcn-2 gene promoter activity by inhibiting Lcn-2 transcription ^[89]. Hence, this provides further evidence that blocking Lcn-2 could be considered a novel strategy for breast cancer therapy.

Furthermore, Lcn-2 was used as a target in a study by Santiago-Sanchez and colleagues, focusing on IBC and modulating Lcn-2 using small interference RNAs (siRNAs) and inhibitors. Although Lcn-2 CRISPR knock-out TNBC cells did not show a difference in cell proliferation, siRNA-mediated Lcn-2 silencing in IBC cells significantly reduced their viability, invasion, proliferation, and migration ^[90]. Moreover, in both cholangiocarcinoma (CCA) and breast cancer cells, the siRNA technology to silence Lcn-2 was tested, whereby in the former study, the knock-down of Lcn-2 in the cholangiocarcinoma cell line RMCCA-1 reduced its metastatic properties in vitro. In addition, cell invasion, migration, Lcn-2/MMP9 complex expression, and pro-MMP9 activities were found to be significantly decreased in the manipulated cells ^[91]. Another study by Guo et al. tested Lcn-2 silencing in combination with targeting C-X-C chemokine receptor type 4 (CXCR4) using liposomes in metastatic TNBC models, MDA-MB-436 and MDA-MB-231, and showed decreased migration of the cells in vitro ^[92].

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