Research ArticleExperimental Studies
Open Access

Interferon-tau (IFN-τ) Has Antiproliferative Effects, Induces Apoptosis, and Inhibits Tumor Growth in a Triple-negative Breast Cancer Murine Tumor Model

ALINA MARIANA ESPIN-RIVERA, FRANCISCO URIEL MEZA-APARICIO, FERNANDO REYNA-FLORES, ANA ISABEL BURGUETE-GARCIA, EDUARDO GUZMAN-OLEA and VICTOR HUGO BERMUDEZ-MORALES
In Vivo November 2023, 37 (6) 2517-2523; DOI: https://doi.org/10.21873/invivo.13359

Abstract

Background/Aim: Resistant triple-negative breast cancer (TNBC) is a subtype of this disease that is resistant to conventional chemotherapy agents. IFN-τ is a cytokine that has recently been shown to have immunoregulatory and antitumor effects. The present study aimed to examine the antiproliferative and apoptosis effects of IFN-τ in breast cancer cells and the antitumor effect in a murine tumor model of TNBC. Materials and Methods: Murine breast cancer 4T1 cells were cultured and treated with ovine IFN-τ and through MTT and Caspase-Glo 3/7 assays, viability and cell death were determined. In addition, the antitumor effect of IFN-τ was determined in a murine tumor model of TNBC. Results: Ovine IFN-τ showed a concentration-dependent antiproliferative effect on 4T1 murine breast cancer cells. Also, treatment of 4T1 cells with IFN-τ induced the activation of caspase 3 and 7, which is indicative of apoptotic cell death. Moreover, we detected an increase in the expression of type I interferon receptor (IFNAR1/2) in cells treated with IFN-. The intratumoral application of IFN-τ in mice inhibited tumor growth compared to the control non-treated group, and the effect was associated with the increased expression of GM-CSF. Conclusion: Ovine IFN-τ may be an effective immunotherapeutic cytokine for the treatment of TNBC.

Key Words:

Breast cancer is the most common neoplasia in women worldwide, with nearly 2.26 million new cases diagnosed in 2020, and 685,000 estimated deaths (1). Breast cancer is a heterogeneous disease whose molecular and clinical characteristics determine the course of the neoplasia, which include the expression or lack of expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth receptor 2 (Her2) (2). However, the resistant triple-negative breast cancer (TNBC) is the most aggressive subtype and is particularly challenging to treat because is not sensitive to endocrine therapies, to treatment directed to the expression of ER, PR, or Her-2 (3). Therefore, the investigation and development of new treatment strategies for TNBC and has become an urgent clinical need.

Furthermore, types I interferons (IFNs) are a group of cytokines that have been proposed as very promising candidates for the treatment of cancer (4). The IFN-α and IFN-β types have been extensively studied for their ability to inhibit tumor cell proliferation through a pro-apoptotic pathway (5). In breast cancer, type I Interferons have been used in receptor-positive cases. When the tumor becomes resistant, one option is treatment with interferon in combination with tamoxifen, IL-2 or other chemotherapeutic drugs; some good results have been obtained, but it is necessary to consider the toxicity and side effects of these treatments (6). TNBC is a heterogeneous group of different treatment-resistant neoplasms with different prognosis. It has been documented that targeting of IFN-β to tumor cells in TNBC can reduce their capacity for migration and tumor formation. The therapeutic effect correlates with interferon (IFN)/signal transducer of activated transcription 1 (STAT1) gene signature (7). Nevertheless, the challenge is to use type I Interferon, maximizing its therapeutic effects in the tumor microenvironment and minimizing systemic side effects.

In addition, other kinds of type I interferons have attracted attention for their low toxicity and therapeutic effects similar to IFN-α and IFN-β. Particularly, tissue culture and animal studies IFN-τ has antiviral, antiproliferative and immunomodulatory activities similar to the type I IFNs, but lacks the toxicity associated with high concentration found in (8). IFN-τ is structurally related to IFN-α and IFN-ω, and trophoblast cells produce it during the peri-implantation period in ruminants (9). Additionally, it displays high species cross-reactivity and functions in various cells, including lymphocytes, macrophages, epithelial tumor cells and antiviral activity (10).

Previous studies have shown that IFN-τ induces an antiproliferative effect and apoptosis in HPV-16 transformed-cells; they also showed tumor growth inhibition in an HPV-16-positive murine tumor model (11). Moreover, the effects of IFN-τ on tumor cells were associated with the MHC Class I, MX and IP10 gene expression (12). However, immunoregulatory mechanisms associated with the antitumor effect of IFN-τ have not yet been studied. Few reports focused on the immunomodulatory properties of IFN-τ. In peripheral blood lymphocytes (PBL) and endometrial epithelial and stromal cells, IFN-τstimulates granulocyte and macrophage colony-stimulating factor (GM-CSF) gene expression (13), which has been shown to promote antitumor immunity in mice and humans (14, 15). It is known that GM-CSF is a critical cytokine for the differentiation of dendritic cells, which are professional antigen-presenting cells and present tumor antigens for the priming of antitumor cytotoxic CD8 T cells (16). This could be a mechanism through which IFN-τ exerts its antitumor effect in the experimental tumor model.

Considering these studies, the main goal of the present study was to examine the antiproliferative and apoptosis effect of IFN-τ in breast cancer cells. In addition, we evaluated its antitumor effect in a murine tumor model of TNBC. We also analyzed whether IFN-τ induces the expression of GM-CSF in vitro and in vivo.

Materials and Methods

Cell lines and reagents. The 4T1 mouse mammary carcinoma cell line was cultured in high glucose DMEM medium supplemented with 10% fetal bovine serum (Invitrogen Thermo Fisher Scientific, Waltham, MA, USA), plus ampicillin- streptomycin (100 U/ml, 10 μ/ml) and L-glutamine (2.9 mg/ml) (all from Caisson Labs, Smithfield, UT, USA) at 37°C in a humidified atmosphere with 5% CO2. Recombinant ovine IFN-τ protein (oIFN-τ) was obtained through Prospec (Rehovot, Israel).

Cell proliferation assay. 4T1 cells were seeded at 1×104 in 96-well plates and were treated with increasing concentrations of oIFN-τ (50 and 100 ng/ml) at 0, 24, 48, and 72 h. Then, cell proliferation was determined using MTT agent (5 mg/ml), and the formazan crystals generated were solubilized with DMSO. The optical density (OD) values were calculated at 540 nm as described previously (11).

Apoptosis assay. Apoptosis in 4T1 breast cancer cells culture treated with oIFN-τ (50 and 100 ng/ml) was determined using the Caspase-Glo 3/7 Assay according to manufacturer’s protocols (G8090; Promega, Madison, WI, USA). The caspase activity was measured using Glomax Multi Microplate Luminometer (Promega). The relative unit values of each assay are presented as the mean±SD of three determinations.

Real Time RT-PCR for IFNAR and GM-CSF. Total RNA was isolated from 4T1 cells treated with oIFN-τ using Qiagen RNA isolation according to the manufacturer’s instructions (Qiagen, Redwood City, CA, USA). One-step Real-time RT-PCR analysis was performed for interferon receptor 1/2 (IFAR1/2) and GM-CSF. RT-qPCR primers and the appropriate TaqMan probe were designed by Universal Probe Library assay design center (Agilent, Santa Clara, CA, USA). The primers pairs using to the PCR reaction were: IFAR1: forward 5′-GCTTCCAGAACTGCTTTTTGA-3′ and Reverse 5′-GGGACTA CATTGCGTCTGC-3′, IFAR2: forward, 5′-CCATCACTACCAAA CACGAAGT-3′ and Reverse 5′-AAAATGCATCGTCCTTCAGC-3′ and GM-CSF forward 5′-TGGCTGTGCCACATCTCTT-3′ and Reverse 5′-TCAG ACTGCTGCTTT TGTGC-3′ and (FAM) TaqMan probe No. 72 (Roche: 04688953001). The amplification reactions were performed using Luna Universal Probe One-Step RT-PCR Kit (New England BioLabs, Ipswich, England) according to the manufacturer’s protocol. The expression of gene transcripts was compared to that of the housekeeping gene GAPDH, VIC-probe, Mm99999915 (Applied Biosystems) and the analysis was based on the 2−ΔΔCt methods.

In vivo experiments. Sixteen-week-old female Balb/c mice (female, 8-10 week-old) were purchased from the National Institute of Public Health Bioterium, Mexico. Mice were anesthetized using anhydrous ether in a closed chamber for 2 min, and 2×105 4T1 cells were injected subcutaneously (s.c.) in the back of Balb/c mice (n=5/group). Tumor volume was measured as previously described (11). Mice with tumor volume of 20 to 30 mm3 were used to evaluate the antitumor effect of ovine IFN-τ and divided into 3 groups. Group A, tumor-bearing mice, was the control group that received only PBS. Group B, tumor-bearing mice treated with 100 ng of ovine IFN-τ diluted in 50 μl of PBS, and Group C, tumor-bearing mice treated with 200 ng of ovine IFN-τ. All mice were monitored for a period of 30 days; three times per week the tumor volume was determined with a digital caliper. The results are expressed as mean diameters±SD.

Statistical analysis. Data were analyzed by using the GraphPad Prism 5 software (Boston, MA, USA). t-test was used to determine statistically significant (p<0.05) between FBS controls or IFN-τ-treated cells. A one-way analysis of variance (ANOVA) was used to compare the significance of differences in tumor-bearing mice treated with oIFN-τ and control groups.

Results

Antiproliferative effect of ovine IFN-τ. To investigate the antiproliferative effects of ovine IFN-τ on 4T1 murine breast cancer cells, we initially screened for type I interferon receptor expression by means of real-time RT-PCR. 4T1 cells were found to express both subunits of the receptor; however, IFN-τ significantly increased expression, resulting in 7 to 10 times higher levels (Figure 1). The expression of subunit 1 (IFNAR1) was the one that was most activated by treatment with IFN-τ. To examine whether IFN-τhas an antiproliferative effect, cultures cells were treated with 100 and 200 ng/ml of interferon and proliferation was detected using the MTT technique, as indicated in the methodology. An antiproliferative effect was observed 24 h after treatment with IFN-τ and was more evident at 72 h where a 50% inhibition was detected at a concentration of 200 ng/ml (p<0.05) (Figure 2).

Figure 1.
Figure 1.

Expression of the IFNAR1 and IFNAR2 following treatment of 4T1 cells with IFN-τ. 4T1 breast cancer cells were treated with ovine IFN-τ (oIFN-τ) for 24 h and the levels of IFNAR1/2 mRNA was determined using real-time RT-PCR.

Figure 2.
Figure 2.

IFN-τ inhibits proliferation of 4T1 cells. 4T1 cells were grown in monolayers and treated with and without 100 and 200 ng of IFN-T for different time periods. Proliferation was assayed using the MTT method as described in Material and Methods. The results are presented as the mean±SD (bars) of three experiments performed in triplicate. The p-values were determined using ANOVA (*p<0.05).

Induction of cell death by ovine IFN-τ in 4T1 cells. To assess whether IFN-τ induces cell death, 4T1 cells were cultured in the presence and absence of IFN-τ. The expression of activated effector caspases 3 and 7, involved in the final step of apoptosis, was analyzed, as indicated in the Materials section. Figure 3 shows that treatment with IFN-τ induces the activation of caspase 3 and 7 in 4T1 cells. Induction of apoptosis was observed at 24 hours and was more evident at 72 h, the time point at 200 ng/ml showed the greatest effect and was statistically significant (p<0.05) (Figure 3).

Figure 3.
Figure 3.

IFN-τ induces apoptosis in 4T1 cells. Apoptosis was determined by analysing the levels of caspase 3/7 activity in cells treated with 100 ng and 200 ng of IFN-τ for 24, 48, and 72 h using Caspase-Glo 3/7 assay. Columns, the means of two experiments; bar, S.D.; 0 untreated control. The p-values were determined using student’s t-test (*p<0.05).

Antitumor effect by IFN-τ in a triple-negative breast cancer murine tumor model. The antitumor effect of IFN-τ was also examined in mice with tumors generated in the back by the implantation of 4T1 cells. The intra-tumoral application of IFN-τ in mice was shown to inhibit tumor growth, both the experimental groups of mice treatment with 100 and 200 ng of IFN-τ compared to the groups without treatment. From day 9, changes in tumor growth were observed the experimental groups, showing only tumor inhibition in mice treated with IFN-τ. It is notable that the 200 ng dose showed a greater effect in delaying tumor growth until day 30 after treatment and this was statistically significant (p<0.05). Figure 4 shows the growth curves of the treated versus control mice.

Figure 4.
Figure 4.

Antitumor effect of IFN-τ in a triple-negative breast cancer murine tumor model. Balb/c mice were subcutaneously (s.c.) inoculated with 2×105 4T1 cells in the back (n=5/group). A, B). Mice with tumor volume of 20-30 mm3 and was the control group and was treated with PBS1X. C, D). Tumor-bearing mice were treated with 100 and 200 ng of ovine IFN-τ diluted in 50 μl of PBS 1X.

Detection of GM-CSF mRNA expression in tumor tissues. To study the mechanism of the effect of IFN-τ in the murine breast cancer antitumor model, the relative mRNA expression levels of GM-CSF gene were analyzed using real-time RT-qPCR in biopsies of tumor tissue. Treatment with IFN-τ, there was a remarkable 25-fold increase in GM-CSF expression, compared to tumor-bearing mice without IFN-τ treatment (p<0.05) (Figure 5). It is very remarkable that 24 h after treatment with IFN-τ, the expression of GM-CSF was increased.

Figure 5.
Figure 5.

CM-CSF mRNA expression in tumor tissues treated with IFN-τ. Tumor-bearing mice were treated with IFN-τ and 24 h after CM-CSF mRNA levels were assayed using real-time RT-PCR in biopsies of tumor tissue. The CM-CSF mRNA expression (tumor-treated/tumor no-treated mice) were normalized with GAPDH gen expression using the 2−ΔΔCT. Bars represent the means and standard errors of three biological replicates, and asterisks indicate p<0.05 (t-test).

Discussion

In the present work, we demonstrated that ovine IFN-τ has a concentration-dependent antiproliferative effect on 4T1 murine breast cancer cells. The percentage of proliferation inhibition in 4T1 cells was between 40-70% at 72 h. Simultaneously, IFN-τ induced activation of caspase 3 and 7, which is indicative of cell death induction in 4T1 cells; similarly, the greatest effect of IFN-τ was detected at 72 h. These results indicate that the TNBC 4T1 cells are susceptible to the action of ovine IFN-τ. Furthermore, IFN-τ significantly increased the expression of IFNAR1/2 receptors, with the type 1 receptor being the one that was most activated. It is known that cell surface IFNAR levels are critical for all IFN effects (17). Interestingly, our study is one of the first reports evaluating the anti-proliferative effect of IFN-τ on a TNBC cell line, and reporting that the levels of IFNAR1/2 can be increased by IFN-τ. The interaction between IFN-τ and the IFNAR1/2 can be analyzed using the STRING program (annexed). Previously, it has been reported that the IFNAR1/2 in ovine endometrial luminal epithelium (LE) and glandular epithelium (GE) cells, appear to be the main targets for IFN-τ (18). However, the association and regulation of IFNAR1/2 expression by IFN-τ in tumor cells and, particularly, in TNBC cells, had not been determined.

In an in vivo study using our TNBC murine tumor model, we observed a set back antitumor effect after treatment with 100 and 200 ng of oIFN-τ. The delay in tumor growth in treated mice was compared to that of the group of untreated tumor-bearing mice and statistically significant difference was observed (p<0.05). It is important to note that 4T1 cells are those that proliferate significantly more rapidly than other tumor cells (17). 4T1 mammary carcinoma is a tumor cell line that is highly tumorigenic, metastatic and invasive, unlike most tumor models (19). Thus, this aggressive characteristic of the TNBC murine tumor makes the delay in tumor growth produced by IFN-τ more significant. Also, IFN-τ has been reported to have immunoregulatory properties activating interferon-stimulated genes (ISGS). It is interesting to note that IFN-τ regulates GM-CSF expression in bovine stromal and leukocyte cells, and favors the regulation of the immune response (20). In our work, treatment of tumor-bearing mice with IFN-τ resulted in a remarkable increase in the gene expression of GM-CSF, and we associate this with the antitumor effect. GM-CSF is a cytokine with multiple immunoregulatory activities including differentiation of granulocytes and macrophages, and recruitment of DCs. It is one of the most potent cytokines that exert long-distance antitumor effects. It has been incorporated as an adjuvant in a variety of cancer vaccines to provide DC-mediated antitumor immunity (21). The expression of GM-CSF in tumor-bearing mice after IFN-τ treatment may partly explain the delay in tumor growth and indicate a possible mechanism implicated in the antitumor effect of IFN-τ in the TNBC murine tumor model. However, we cannot rule out other mechanisms involved in the antitumor effect. In the present study, we only focused on the antiproliferative and anti-tumor effect of oIFN-τ in 4T1 cells and the TNBC murine tumor model. Although treatment with IFN-τ alone will not eliminate tumors, it is necessary to increase the dose or combine the treatment with another adjuvant to eradicate the tumor. We also still need to explore other mechanisms implicated in the antitumor effect, such as, the possibility of reactivating the IFN-I response as a potential therapy in tripe-negative breast cancer (22).

Importantly, IFNs has been successfully used to treat some tumors, but for the breast cancer treatment it has been limited and effective due in part to toxicity from doses (23). Reports on the high doses of IFNs are required to generate an antiproliferative and antitumor effects in vitro and in vivo models of breast cancer limit its application in clinical trails (24). In this way, ovine IFN-τ is a unique type I interferon with low toxicity even in high concentrations, is promising for the treatment of breast cancer, other types of solid tumors and viral diseases (25).

In summary, we found that oIFN-τ shows antiproliferative effect in 4T1 murine breast cancer cells and the induction of apoptosis, as well as with the activation of the expression of the IFNAR1/2. Furthermore, delay of tumor growth and expression of GM-CSF was observed in a TNBC murine tumor model after the treatment with oIFN-τ. However, it is critical to clarify the mechanism by which oIFN-τ exerts these effects on cells, including signal transduction, immunoregulatory effects, activation of the dendritic cells and profile cytokines regulated by the IFN-τ, before it can be proposed as a promising protein for breast cancer immunotherapy.

Acknowledgements

This work was supported by a Grant from the National Council of Science and Technology (CONACYT) (Conacyt-Proyectos de Desarrollo Científico para Atender Problemas Nacionales-2013-215484).

Footnotes

  • Authors’ Contributions

    VHB: Was involved in study conception and design. AMER and FUMA: Were involved in data acquisition. LFR and AB: Analyzed and interpreted data. AB, EGO, VHB wrote this manuscript. All Authors reviewed and approved the manuscript.

  • Conflicts of Interest

    The Authors have no conflicts of interest to declare in relation to this study.

  • Received March 9, 2023.
  • Revision received August 1, 2023.
  • Accepted August 3, 2023.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Interferon-tau (IFN-τ) Has Antiproliferative Effects, Induces Apoptosis, and Inhibits Tumor Growth in a Triple-negative Breast Cancer Murine Tumor Model
ALINA MARIANA ESPIN-RIVERA, FRANCISCO URIEL MEZA-APARICIO, FERNANDO REYNA-FLORES, ANA ISABEL BURGUETE-GARCIA, EDUARDO GUZMAN-OLEA, VICTOR HUGO BERMUDEZ-MORALES
In Vivo Nov 2023, 37 (6) 2517-2523; DOI: 10.21873/invivo.13359
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