Abstract
Purpose
Macrophage migration inhibitory factor (MIF) is an integral cytokine for the modulation of both innate and adaptive immunity and is involved in the pathogenesis of various cancers. However, conflicting findings on the relationship between MIF polymorphisms and breast cancer (BC) have been reported in earlier research. We investigated the clinical value of serum MIF levels and the association between MIF rs1049829 and rs755622 variants with their serum levels and propensity to develop BC.
Methods
A total of 133 treatment-naïve Egyptian BC females and 126 apparently healthy controls were matriculated in this case–control study. The serum MIF protein levels were quantified by ELISA, whereas the genotyping was executed utilizing the TaqMan® allelic discrimination assay.
Results
A significant increase in the serum MIF level in BC cases was observed in comparison to control subjects (P < 0.0001), with a diagnostic potential to discriminate BC with 92.5% sensitivity and 73.7% specificity at a cut-off value > 9.47 ng/mL. Besides, a significant difference in serum MIF level was observed in BC cases with progesterone receptor (PR) negativity compared to those with PR positivity (P = 0.046). Moreover, a significant association was depicted between the rs1049829 variant of MIF gene and the protective effect against BC meanwhile the rs755622 variant demonstrated no significant link with BC risk.
Conclusions
This study revealed that serum MIF levels may be regarded as a promising serum tumor marker for BC. Also, the rs1049829 variant of the MIF gene is considered a protective candidate against BC.
Graphical Abstract
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Breast cancer (BC) is the utmost regularly diagnosed malignancy, with an assessed 2.3 million diagnoses and 685,000 fatalities from cancer worldwide in 2020 [1]. The BC mortality rates are considerably increasing in developing countries, including Egypt, which represents 10.8% of total cancer cases [2]. The incidence of BC has noticeably elevated, particularly amongst young females, and its global annual incidence is envisioned to reach 4.4 million in 2070 [3]. Diagnosing BC in women at earlier stages can noticeably enhance the survival rate and the BC prognosis is intensely complicated by late diagnosis [4].
Interestingly, several epidemiological studies revealed that patients enduring chronic inflammatory diseases have an amplified risk for cancer incidence. Besides, it is estimated that about 30% of cancer incidence in low- and middle-income nations is related to microbial infections [5]. With regard to the action of inflammatory mediators in endorsing oncogenesis and tumor progression, evidence is pointing towards a probable correlation amongst macrophage migration inhibitory factor (MIF) expression and tumorigenesis and cancer progression [6].
Macrophages, which have a fundamental function in immune response, were described as a fundamental contributor throughout the oncogenesis process by endorsing tumor cell proliferation, survival, and migration [6, 7]. The MIF gene is located on chromosome 22q11.2 and is considered as a subcomponent of the transforming growth factor-β (TGF-β) superfamily. MIF is released by several cells comprising macrophages, granulocytes, T and B lymphocytes, endothelial cells, as well as cancer cells [8]. The MIF is regarded as a proinflammatory cytokine and contributes in the progress of oncogenesis by endorsing tumor development, altering immunological responses, enhancing inflammation, and aiding cancer-associated angiogenesis [6, 7]. A study by Verjans et al. revealed that MIF protein has a dual role in BC development. Increased MIF protein expression inside the BC cells is beneficial and protective, while increased serum levels of MIF protein are prooncogenic [9].
Some studies reported that the MIF gene rs755622-G/C polymorphism is associated with the amplified solid tumor risk [10] and BC risk [11, 12]. However, the study by Avalos‐Navarro et al. failed to find a notable association in the Mexican‐mestizo population [8]. On the other hand, the rs1049829 variant of MIF gene has been studied for a possible correlation with colorectal cancer risk, but no significant association was found [13]. However, no previous studies were performed to report its association with BC.
There is still no research focusing on the relationship between MIF gene polymorphism and BC susceptibility in Egyptian females. Thus, we investigated the serum MIF levels for the first time in Egyptian BC patients and the association between both MIF gene rs1049829 and rs755622 variants with BC susceptibility.
Patients and methods
Subjects
Between December 2022 and March 2023, blood samples were drawn from 133 consecutive treatment-naïve primary BC female patients aged ≥ 18 years who presented to the Medical Oncology Department of the National Cancer Institute of Cairo University, and from 126 healthy females as a control group. Ages were closely matched as feasible between the patient and control groups; the median age of the former group was 50 years (range: 18–65). A definite diagnosis of BC was employed by clinical examination, mammography and confirmed by histopathology. Patients’ demographics and clinicopathological data are presented in Table 1 and Table 2, respectively. Disease stage and tumor grade were based on the American Joint Committee on Cancer (AJCC) [14] and grading approach [15], respectively. We included any disease stage at presentation then patients were divided into two groups: curative stage (I, II, and III) and metastatic stage (IV). According to St. Gallen BC expert consensus [16] and owing to deficient Ki67% information in some BC cases, the remaining patients were classified using immunohistochemistry into classes: luminal A: (ER + and PR + , HER2−, and low-Ki67 index), Luminal B (HER2 negative): (ER + , HER2−, and at least one of high Ki67 or PR-/low), Luminal B (HER2 positive): (ER + , HER2 over-expressed or amplified, and any Ki67 or any PR), triple-negative BC (TNBC): (ER−, PR−, & HER2−), and HER2−enriched (ER−, PR− & HER2+) (Table 2). The existing prospective case–control study was conducted based on the ethical principles of the Helsinki Declaration and was approved by the National Cancer Institute’s Institutional Review Board (IRB), located at Cairo University (Cairo, Egypt), IRB approval no. (2212-5051-0443). In advance, the study protocol was explained to every subject in both written and conversational form. Also, control participants and BC patients signed written informed consents. Exclusion criteria included patients with autoimmune diseases, morbid obesity, tobacco users, or those who received immunomodulators. Healthy female controls were recruited from women whose annual physical examinations revealed no cancer.
Sampling
After the final diagnosis, 6 mL of venous blood specimen was obtained from each subject. 3 mL was collected in a vacutainer tube containing EDTA and stored at −80 °C at Al-Azhar University’s Molecular Biology laboratory until the time of DNA extraction. The other 3 ml was collected in a gel vacutainer tube for serum isolation and used for the determination of serum MIF level.
Measurement of serum MIF levels
Serum MIF levels were quantified by a sandwich enzyme-linked immunosorbent assay (ELISA) utilizing a commercial human MIF ELISA kit supplied by Elabscience®, Texas, USA (Cat. No: E-EL-H1530) adhering to the producer’s instructions. The optical density was determined utilizing a microplate reader (Stat Fax® 2100, Awareness Technology, USA) set to 450 nm.
DNA extraction and genotyping
Utilizing the GeneJET™ DNA purification kit (Thermo scientific, USA), genomic DNA was isolated and purified from subjects’ EDTA whole blood. Aliquots of DNA were then kept at −80 °C until analysis. By measuring DNA’s optical density at 260 nm with a Thermo Scientific NanoDrop 2000 spectrophotometer (Wilmington, USA), the concentration of DNA was calculated. At 260/230 nm and 260/280 nm optical density ratios, the purity of DNA was evaluated. Genotyping of MIF single nucleotide polymorphisms (SNPs) rs755622 and rs1049829 was investigated utilizing a TaqMan® allelic discrimination analysis by design provided by Applied Biosystems, Foster City, USA. The manufacturer’s directions and commonly available probes and primers were applied to conduct this investigation employing an Applied Biosystems International Step One real-time PCR apparatus (Foster City, USA) in a volume for each reaction of 20 μL.
Sample size
Based on Avalos‐Navarro et al. study [8], a sample size of 108 subjects per group was calculated according to the minor allele frequencies of the MIF rs755622 and 1049829 to detect power of 80% and type 1 error = 0.05. Sample size estimation was performed by the PS statistical package.
Statistical analysis
All statistical assessment was conducted utilizing Graph pad prism (version 9, Inc, USA). The Kolmogorov–Smirnov and Shapiro–Wilk normality tests were applied. The medians and ranges were used to represent quantitative values. On the other hand, numbers (n) and percentages (%) were utilized to describe qualitative values. Concerning non-parametric data, the Kruskal–Wallis test was utilized to evaluate the differences across the various studied groups, and if necessary, the Dunn’s adjustment test was performed. Also, the Mann–Whitney U test was applied to evaluate the difference between the two studied groups. Utilizing the receiver operating characteristic (ROC) curve for evaluating the diagnostic accuracy of serum MIF levels, the optimal cut-off point, sensitivity, specificity, as well as area under the curve (AUC) were assessed. Regarding the qualitative data comparison and Hardy–Weinberg equilibrium (HWE) test and genetic association of MIF rs755622 and rs1049829 with risk to BC, the Chi-square test (χ2) was employed. For the risk alleles, odds ratios (ORs) and 95% confidence interval (95% CI) were assessed. SHEsis software (http://shesisplus.bio-x.cn/) was applied for haplotype analysis and investigating the interaction of the two MIF SNPs with the BC susceptibility. The criterion for statistical significance was established at p < 0.05. Our research adheres to Reporting recommendations for tumor marker prognostic studies (REMARK) standards [17]
Results
The current study comprised 259 females (133 BC patients and 126 healthy controls). The age distributions of the BC patients and controls were matched. In addition, there was no notable difference in menopausal status between the 2 investigated groups (Table 1). Clinicopathologic features of BC cases are summarized in Table 2.
The serum level of MIF was significantly increased in the BC cases in comparison to the control subjects (p < 0.0001), with a diagnostic potential to discriminate BC with a sensitivity of 92.5% and a specificity of 73.7% at a cut-off value > 9.47 ng/mL (Fig. 1).
Regarding the comparison of cancer grades and TNM stages in BC patients, there was no notable difference in serum MIF level that was observed. However, a significant increase was demonstrated in BC patients with various TNM stages I, II, III, and IV in contrast to control females with p values 0.0002, < 0.0001, < 0.0001, and < 0.0001, respectively (Fig. 2A). Also, a significant elevation in serum MIF level was revealed in BC patients with curative and metastatic stages in contrast to control females, with p values < 0.0001 and < 0.0001 respectively, while no notable difference in serum MIF levels was demonstrated between BC cases with curative and metastatic stages (Fig. 2B).
Owing to the lack of Ki67 data in 48 BC cases, we were unable to classify those patients according to luminal subclassification; however, no marked difference in serum MIF level was observed between BC molecular subtypes in the rest of the cases (P = 0.126). Besides, a notable significant difference in serum MIF level in PR-negative compared to PR-positive BC patients (P = 0.046), while there was no notable difference observed regarding ER and HER2 expression. Moreover, the statistical findings showed that there was no significant change in serum MIF levels amongst BC patients with various pathological tumor stages (p = 0.69) and nodal status (p = 0.28) (Table 2).
Genotype distributions of the MIF gene rs1049829 and rs755622 variants were in accordance with Hardy–Weinberg equilibrium (p > 0.05) as demonstrated in Tables 3, 4 Interestingly, a significant association between the T allele of rs1049829 variant of MIF gene and the protective effect against BC (OR = 0.51, 95% CI = 0.34–0.77, p = 0.001). Besides, a notable association with a protective effect against BC was observed under the two codominant models (CT versus CC, OR = 0.46, 95% CI = 0.27–0.76 p = 0.003, and TT versus CC, OR = 0.24, 95% CI = 0.06–0.85 p = 0.03), the dominant model (OR = 0.43, 95% CI = 0.26–0.72, p = 0.001). Moreover, a significant association with the risk of BC was revealed only under the over-dominant model (OR = 1.95, 95% CI = 1.16–3.22, p = 0.008), while the recessive model showed no significant association with BC risk (p = 0.10) (Table 3).
On the other hand, the statistical data showed no notable association amongst the rs755622 variant of MIF gene and the susceptibility of BC (p = 0.39). Moreover, no significant association with the risk of BC was observed under the different genetic models used in this study which include the two codominant (GC versus GG, p = 0.45 and CC versus GG, p = 0.56), dominant (p = 0.4), recessive (p = 0.61), and over-dominant (p = 0.48) (Table 4).
To clarify the association amongst interactions of the two studied MIF SNPs and BC, we have carried out a haplotype analysis performed with in silico analysis by SHEsis software. As a result, the rs755622-G and rs1049829-T haplotypes showed a significant association with a protective impact against BC (OR = 0.51, 95% CI = 0.34–0.79, p = 0.002), while other haplotype frequencies showed no significant association with BC risk (Table 5).
In addition, we have investigated the association between serum MIF level and the two investigated MIF SNPs rs755622 and rs1049829 in BC patients, and no statistical association was observed with p values 0.1123 and 0.8455, respectively (Fig. 3).
Discussion
Breast cancer is the foremost determinant of cancer mortality in females [1]. Successful cancer treatment requires the development of early-stage cancer diagnostic techniques and the assessment of a patient’s risk of cancer progression and recurrence [18]. Several studies have informed that the existence of genetic factors, such as mutations and SNPs, increases the risk for the development and progression of BC [19], as well as those found in the proinflammatory cytokine MIF gene [11]. The contribution of the MIF alleles in the progression of cancer was correlated and reported in different types of cancers such as hepatocellular carcinoma [20], gastric cancer [21], BC [11], and prostate cancer [22]. This is the first study, to our knowledge, to assess the allelic and genotypic frequencies of (rs1049829) and (rs755622) polymorphisms of MIF gene in women with BC in the Egyptian population.
To the best of our knowledge, the association between the MIF gene rs1049829 and BC risk has not been previously studied. This study describes a significant correlation between the rs1049829 variant of the MIF gene and the protective effect against BC in women from the Egyptian population. Although a study by Ramireddy et al. found no notable correlation amongst this polymorphism and the susceptibility to colorectal cancer in the Taiwan population [13]. This discrepancy may be referred to differences in cancer type, sample size, age, and race.
Consistent with our findings, a study by Avalos‐Navarro et al. evaluated the MIF gene rs755622-G/C polymorphism in women with BC in the Mexican population and showed no significant correlation with BC risk [8]. Conversely, a study by Lin et al. showed a notable association between the rs755622 variant of the MIF gene and BC susceptibility in women of the Chinese population [11]. Further studies found a protective effect for this SNP against colorectal cancer [23] and bladder cancer risks [24, 25]. These disagreements may be credited to the criteria for inclusion, sample size, and racial variances amongst nations. Also, some findings from earlier research should be interpreted cautiously because not all genetic models have been evaluated in these investigations.
In accordance with other reports [8, 26, 27], the serum MIF level in BC patients is markedly elevated than that in control subjects, suggesting that MIF has a marked role in endorsing oncogenesis. Furthermore, we demonstrated that serum MIF has the diagnostic potential to distinguish between BC patients and healthy controls at a cut-off value of > 9.47 ng/mL with a 92.5% sensitivity and 73.7% specificity. In harmony with our results, Ciftci et al., observed a significant difference in serum MIF level between BC cases and control group, with a mean level of 10.7 and 5.49 ng/mL, respectively. Also, they revealed a discriminating power of serum MIF level between BC patients and healthy individuals at a cut-off value of 1.1275 ng/ml with sensitivity and specificity of 97% and 71%, respectively [27]. The difference between our observed cut-off value and that of Ciftci et al. may be attributed to the difference in age of recruited subjects and sample size where Ciftci et al. recruited only 28 control subjects and 96 BC cases. Besides, Fersching et al. revealed a discriminating ability of MIF between BC patients and healthy individuals, and between metastatic BC patients and BC patients with locally confined, with AUC 70.7% and 87.6%, respectively [28]. Similarly, MIF was found to be a possible diagnostic marker for gastric cancer at a cut-off value of 3.23 ng/mL with 83.5% sensitivity, 92.3% specificity, and 89.7% accuracy [29]. While the difference observed in cut-off value may be attributed to the difference in cancer type, gender recruitment, and patient demographics. Moreover, Richard et al. revealed a marked increase in the expression level of MIF protein inside the BC tissue describing MIF as a marker to discriminate normal tissue from BC tissue by immunohistochemistry [30]. These findings might enhance the potentiality of serum MIF level as a diagnostic tumor marker for BC, point out MIF as a possible therapeutic target for pharmacological modulators, and indicate the evidence that cytokines are spawned by immune and tumor cells.
Interestingly, the primary source of MIF in tumors is the epithelial cells themselves, with a little secretory supply from stromal and inflammation-related cells, as well as other components of the tumor microenvironment. Notably, the cytokine MIF drives oncogenesis by supporting tumor growth, regulating immunological responses, boosting inflammation, and promoting tumor-associated angiogenesis [31, 32]. Also, MIF enhances the cancerous microenvironment by inducing inflammation and releasing inflammatory mediators like tumor necrosis factor α, interleukin (IL)-1β, and IL-6 [33].
The present study hasn’t found a statistical significance in serum MIF levels between different grades and stages of BC. These results are endorsed by several studies that reported that neither MIF expression in BC tissue [30, 34] nor serum MIF level [30] showed statistically significant differences between different tumor grades. However, results obtained by Avalos-Navarro et al. revealed a statistically significant elevation in serum MIF levels in BC cases with advanced stages compared to those with stage I [35]. This contrasting finding may be attributed to the difference in the sample size, patients’ inclusion criteria, and the utilized kit.
Furthermore, we depicted that elevated serum MIF levels were associated with PR negativity, this result comes in harmony with other reports that showed that the expression of the MIF gene is elevated in cells with negative hormonal receptors [9, 35, 36]. Such finding might signify that MIF is a probable marker for aggressive BC conditions characterized by poor prognosis, recurrence, metastasis, and lack of specific therapeutic targets [37], suggesting a potential use of anti-MIF agents, such as Imalumab which is still processed in clinical trials and showing promising antitumor activity in patients with advanced solid tumors. Imalumab increases apoptosis by suppressing MIF-induced phosphorylation of ERK1/2 and AKT. Imalumab also makes cancer cell lines more susceptible to cytotoxic medications [38]. Moreover, in clinical practice, serum MIF levels could be utilized to stratify patients based on the aggressiveness of their disease, potentially guiding treatment decisions. This stratification could inform the choice and intensity of therapeutic interventions.
In addition, we have evaluated the probable relationship amongst the functional variants of the MIF gene (rs755622 and rs1049829) with the serum levels of MIF protein in women with BC and showed no significant variation in serum MIF levels neither the BC patients with rs1049829 TT and CT versus CC nor rs755622 CC and GC versus GG. There are limitations in this study, Ki67 data were lacking for some BC patients which decreased the number of cases in the molecular subtyping; moreover, this case–control study did not clarify the underlying mechanisms beyond the effect of MIF polymorphisms on BC risk. Therefore, laboratory validation both in vivo and in vitro is envisioned to illuminate the detailed molecular mechanism, and prospective clinical validation with studies involving larger cohorts of breast cancer patients is required to confirm the prognostic value of serum MIF levels. These studies should aim to correlate serum MIF levels with clinical outcomes, including response to treatment and overall survival.
Conclusions
The findings of this research proposed that serum MIF level may be considered a helpful tumor marker of BC. Also, the rs1049829 variant of MIF gene is considered a protective candidate against BC whereas the rs755622 variant is not regarded as a genetic risk factor for BC amongst Egyptian patients. Moreover, the MIF gene haplotype (rs1049829-T and rs755622-G) showed a significant association with a protective effect against BC.
Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Abbreviations
- AJCC:
-
American joint committee on cancer
- AUC:
-
Area under the curve
- BC:
-
Breast cancer
- ELISA:
-
Enzyme-linked immunosorbent assay
- ER:
-
Estrogen receptor
- G:
-
Grade
- HER2:
-
Human epidermal growth factor receptor 2
- HWE:
-
Hardy–Weinberg equilibrium
- IRB:
-
Institutional Review Board
- IDC:
-
Invasive ductal carcinoma;
- ILC:
-
Invasive lobular carcinoma
- MIF:
-
Macrophage migration inhibitory factor
- pN:
-
Pathological node
- PR:
-
Progesterone receptor
- pT:
-
Pathological tumor
- ROC:
-
Receiver operating characteristic
- SNPs:
-
Single nucleotide polymorphisms
- TGF-β:
-
Transforming growth factor-β
- TNBC:
-
Triple negative breast cancer
- TNFα:
-
Tumor necrosis factor alpha
- TNM:
-
Tumor-node-metastasis
References
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: Cancer J Clin. https://doi.org/10.3322/caac.21660
Cancer Egypt 2020 country profile [https://www.who.int/publications/m/item/cancer-egy-2020]
Soerjomataram I, Bray F (2021) Planning for tomorrow: global cancer incidence and the role of prevention 2020–2070. Nat Rev Clin Oncol 18(10):663–672. https://doi.org/10.1038/s41571-021-00514-z
Brandt J, Garne JP, Tengrup I, Manjer J (2015) Age at diagnosis in relation to survival following breast cancer: a cohort study. World J Surg Oncol 13:1–11
World Health organization’s cancer newsroom [https://www.who.int/news-room/fact-sheets/detail/cancer]
Grieb G, Merk M, Bernhagen J, Bucala R (2010) Macrophage migration inhibitory factor (MIF): a promising biomarker. Drug News Perspect 23(4):257
Richard V, Kindt N, Saussez S (2015) Macrophage migration inhibitory factor involvement in breast cancer. Int J Oncol 47(5):1627–1633
Avalos-Navarro G, Del Toro-Arreola A, Daneri-Navarro A, Quintero-Ramos A, Bautista-Herrera LA, Franco Topete RA, Anaya Macias BU, Javalera Castro DI (2020) Morán-Mendoza AdJ, Oceguera-Villanueva A: association of the genetic variants (−794 CATT5-8 and −173 G> C) of macrophage migration inhibitory factor (MIF) with higher soluble levels of MIF and TNFα in women with breast cancer. J Clin Lab Anal 34(5):e23209. https://doi.org/10.1002/jcla.23209
Verjans E, Noetzel E, Bektas N, Schütz AK, Lue H, Lennartz B, Hartmann A, Dahl E, Bernhagen J (2009) Dual role of macrophage migration inhibitory factor (MIF) in human breast cancer. BMC Cancer 9:1–18. https://doi.org/10.1186/1471-2407-9-230
Vera PL, Meyer-Siegler KL (2011) Association between macrophage migration inhibitory factor promoter region polymorphism (−173 G/C) and cancer: a meta-analysis. BMC Res Notes 4:1–5
Lin S, Wang M, Liu X, Zhu W, Guo Y, Dai Z, Yang P, Tian T, Dai C, Zheng Y (2017) Association of genetic polymorphisms in MIF with breast cancer risk in Chinese women. Clin Exp Med 17:395–401
Pehlivan S, Işiksaçan N, Pehlivan M, Günaldi M, Oyaci Y, Nursal AF (2020) The MIF rs755622 variant may increase susceptibility of breast cancer but not gastrointestinal cancer in a turkish population. Turk J Oncol. https://doi.org/10.5505/tjo.2020.2186
Ramireddy L, Chen WTL, Peng CT, Hu RM, Ke TW, Chiang HC, Chang SC, Tsai FJ, Lo WY (2015) Association between genetic polymorphism of the MIF gene and colorectal cancer in Taiwan. J Clin Lab Anal 29(4):268–274
Amin MB, Greene FL, Edge SB, Compton CC, Gershenwald JE, Brookland RK, Meyer L, Gress DM, Byrd DR, Winchester DP (2017) The eighth edition AJCC cancer staging manual: continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin. https://doi.org/10.3322/caac.21388
Elston CW, Ellis IO (1991) Pathological prognostic factors in breast cancer I the value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathol. https://doi.org/10.1111/j.1365-2559.1991.tb00229.x
Goldhirsch A, Winer EP, Coates A, Gelber R, Piccart-Gebhart M, Thürlimann B, Senn H-J, Albain KS, André F, Bergh J (2013) Personalizing the treatment of women with early breast cancer: highlights of the St Gallen international expert consensus on the primary therapy of early breast cancer 2013. Ann Oncol 24(9):2206–2223
McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2005) Statistics subcommittee of the NCIEWGoCD, reporting recommendations for tumor marker prognostic studies. J Clin Oncol. https://doi.org/10.1200/JCO.2004.01.0454
Hartwell L, Mankoff D, Paulovich A, Ramsey S, Swisher E (2006) Cancer biomarkers: a systems approach. Nat Biotechnol 24(8):905–908. https://doi.org/10.1038/nbt0806-905
Dite GS, Mahmoodi M, Bickerstaffe A, Hammet F, Macinnis RJ, Tsimiklis H, Dowty JG, Apicella C, Phillips K-A, Giles GG (2013) Using SNP genotypes to improve the discrimination of a simple breast cancer risk prediction model. Breast Cancer Res Treat 139:887–896
Yuan T, Tang C, Chen M, Deng S, Chen P (2013) Influence of the human MIF promoter polymorphism on hepatocellular carcinoma prognosis. Genet Mol Res 12(4):6629–6635
Ni P, Wang G, Wang Y, Liu K, Chen W, Xiao J, Fan H, Ma X, Li Z, Shen K (2022) Correlation of MIF-AS1 polymorphisms with the risk and prognosis of gastric cancer. Pathol Res Pract 233:153850
Meyer-Siegler K, Vera P, Iczkowski K, Bifulco C, Lee A, Gregersen P, Leng L, Bucala R (2007) Macrophage migration inhibitory factor (MIF) gene polymorphisms are associated with increased prostate cancer incidence. Genes Immun 8(8):646–652
Moundir C, Chehab F, Senhaji N, Boufettal R, Idouz K, Erguibi D, Nadifi S (2019) Association of the IL-17A rs2275913 and MIF rs755622 polymorphisms with the risk of gastric and colorectal cancer. Meta Gene 22:100605. https://doi.org/10.1016/j.mgene.2019.100605
AlChalabi R, Mahdi S, Fadhil A, Jawad H (2016) Polymorphism in the promoter region of MIF and risk of bladder cancer in Iraqi patients. Int J Sci Basic Appl Res (IJSBAR) 24:84–93
Yuan Q, Wang M, Wang M, Zhang Z, Zhang W (2012) Macrophage migration inhibitory factor gene-173G> C polymorphism and risk of bladder cancer in southeast China: a case–control analysis. Mol Biol Rep 39:3109–3115. https://doi.org/10.1007/s11033-011-1075-9
Bando H, Matsumoto G, Bando M, Muta M, Ogawa T, Funata N, Nishihira J, Koike M, Toi M (2002) Expression of macrophage migration inhibitory factor in human breast cancer: association with nodal spread. Jpn J Cancer Res 93(4):389–396
Ciftci R, Tas F, Aksit E, Vatansever S, Karabulut S, Sen F, Yildiz I, Keskin S, Bozbey HU, Kilic L (2014) Clinical significance of serum macrophage migration inhibitory factor (MIF) level in breast cancer. In Am Soc Clin Oncol. https://doi.org/10.1200/jco.2014.32.15_suppl.e11556
Fersching DM, Nagel D, Siegele B, Salat C, Heinemann V, Holdenrieder S, Stoetzer OJ (2012) Apoptosis-related biomarkers sFAS, MIF, ICAM-1 and PAI-1 in serum of breast cancer patients undergoing neoadjuvant chemotherapy. Anticancer Res 32(5):2047–2058
Xia HHX, Yang Y, Chu KM, Gu Q, Zhang YY, He H, Wong WM, Leung SY, Yuen ST, Yuen MF (2009) Serum macrophage migration-inhibitory factor as a diagnostic and prognostic biomarker for gastric cancer. Cancer 115(23):5441–5449
Richard V, Kindt N, Decaestecker C, Gabius HJ, Laurent G, Noel J-C, Saussez S (2014) Involvement of macrophage migration inhibitory factor and its receptor (CD74) in human breast cancer. Oncol Rep 32(2):523–529
Klemke L, De Oliveira T, Witt D, Winkler N, Bohnenberger H, Bucala R, Conradi L-C, Schulz-Heddergott R (2021) Hsp90-stabilized MIF supports tumor progression via macrophage recruitment and angiogenesis in colorectal cancer. Cell Death Dis 12(2):155
Noe JT, Mitchell RA (2020) MIF-dependent control of tumor immunity. Front Immunol 11:609948. https://doi.org/10.3389/fimmu.2020.609948
Esquivel-Velázquez M, Ostoa-Saloma P, Palacios-Arreola MI, Nava-Castro KE, Castro JI, Morales-Montor J (2015) The role of cytokines in breast cancer development and progression. J Interf Cytokine Res 35(1):1–16. https://doi.org/10.1089/jir.2014.0026
Xu X, Wang B, Ye C, Yao C, Lin Y, Huang X, Zhang Y, Wang S (2008) Overexpression of macrophage migration inhibitory factor induces angiogenesis in human breast cancer. Cancer Lett 261(2):147–157
Avalos-Navarro G, Muñoz-Valle JF, Daneri-Navarro A, Quintero-Ramos A, Franco-Topete RA, Morán-Mendoza AdJ, Oceguera-Villanueva A, Bautista-Herrera LA, Topete-Camacho A, Del Toro-Arreola A (2019) Circulating soluble levels of MIF in women with breast cancer in the molecular subtypes: relationship with Th17 cytokine profile. Clin Exp Med 19(385):391
Charan M, Das S, Mishra S, Chatterjee N, Varikuti S, Kaul K, Misri S, Ahirwar DK, Satoskar AR, Ganju RK (2020) Macrophage migration inhibitory factor inhibition as a novel therapeutic approach against triple-negative breast cancer. Cell Death Dis 11(9):774
Cui X, Schiff R, Arpino G, Osborne CK, Lee AV (2005) Biology of progesterone receptor loss in breast cancer and its implications for endocrine therapy. J Clin Oncol 23(30):7721–7735
Mahalingam D, Patel MR, Sachdev JC, Hart LL, Halama N, Ramanathan RK, Sarantopoulos J, Völkel D, Youssef A, de Jong FA (2020) Phase I study of imalumab (BAX69), a fully human recombinant antioxidized macrophage migration inhibitory factor antibody in advanced solid tumours. Br J Clin Pharmacol 86(9):1836–1848
Acknowledgements
We are deeply grateful to the Al-Azhar University in Cairo, Faculty of Pharmacy’s Biochemistry and Molecular Biology Department for supplying the lab tools and collaborating.
Funding
Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB). This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Author information
Authors and Affiliations
Contributions
A.M.M., A.A.E., M.I.K.E, and M.A.S. contributed to the study’s conception and design. YI was responsible for patients’ recruitment, diagnosis, and clinicopathologic data collection. A.M.M., A.A.E., M.I.K.E, YI, and M.A.S. contributed to methodology and manuscript writing. A.A.E. and M.A.S. contributed to statistical analysis and investigation. All authors read and approved the final version of the manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare they have no conflict of interest.
Ethical approval
The study was conducted in accordance with the ethical principles of the Helsinki Declaration and was approved by the Institutional Review Board (IRB) of the National Cancer Institute, Cairo University, Cairo, Egypt, with IRB approval number (2212–5051-0443).
Consent to participate
The signed written informed consent of both controls and cases was collected in advance.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Seliem, M.A., Mohamadin, A.M., El-Sayed, M.I.K. et al. The clinical signature of genetic variants and serum levels of macrophage migration inhibitory factor in Egyptian breast cancer patients. Breast Cancer Res Treat (2024). https://doi.org/10.1007/s10549-024-07393-9
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s10549-024-07393-9