Zhang et al. J Transl Med (2020) 18:247 https://doi.org/10.1186/s12967-020-02420-x Journal of Translational Medicine

REVIEW Open Access Involvement of in the occurrence and development of breast cancers Man‑Li Zhang1†, Hua‑Tao Wu2†, Wen‑Jia Chen1,3, Ya Xu1, Qian‑Qian Ye1,3, Jia‑Xin Shen4 and Jing Liu1,3*

Abstract Glutathione peroxidases (GPxs) belong to a family of that is important in organisms; these enzymes pro‑ mote metabolism and protect cell membrane structure and function from oxidative damage. Based on the establishment and development of the theory of the pathological roles of free radicals, the role of GPxs has gradually attracted researchers’ attention, and the involvement of GPxs in the occurrence and development of malignant tumors has been shown. On the other hand, the incidence of breast cancer in increasing, and breast cancer has become the leading cause of cancer-related death in females worldwide; breast cancer is thought to be related to the increased production of reactive oxygen species, indicating the involvement of GPxs in these processes. Therefore, this article focused on the molecular mechanism and function of GPxs in the occurrence and development of breast cancer to understand their role in breast cancer and to provide a new theoretical basis for the treatment of breast cancer. Keywords: Glutathione , Breast cancer, Reactive oxygen species, Occurrence

Background [4]. However, the mechanisms of the occurrence, devel- Breast cancer has become the most common cancer and opment, and metastasis of breast cancer are very com- the leading cause of cancer-related deaths in females plicated and overlap, suggesting the necessity of diferent worldwide, according to a status report on the global therapies to treat diferent subtypes of breast cancer. To cancer burden provided by Globocan 2018 [1]. Te cur- achieve the best treatment efect, it is necessary to adopt rent standard treatment for patients with breast cancer a customized treatment plan for patients, based on the includes the combination of surgery, radiation, hormone understanding of the pathogenesis of breast cancer [5, 6]. therapy and chemotherapy drugs, such as anthracy- Recent studies have shown that reactive oxygen spe- clines, cyclophosphamide, taxanes and platinum com- cies (ROS) are involved in the molecular mechanisms of pounds [2, 3]. As a superfcial tumor, the causes of death breast cancer occurrence and development [7–9]; ROS in patients with breast cancer are reported to be due to can be regulated by glutathione peroxidases (GPxs), cancer metastasis and/or relapse, which are signifcantly which are the key enzymes that maintain ROS homeo- associated with the favorable tumor microenvironment stasis in vivo through the reduction of ROS [10]. Tere- fore, based on summaries of the research regarding the relationship between breast cancer and GPxs, this article *Correspondence: [email protected] †Man-Li Zhang and Hua-Tao Wu contributed equally to this work focused on the molecular mechanism and function of 1 Changjiang Scholar’s Laboratory/Guangdong Provincial Key Laboratory diferent GPxs and their diverse roles in the occurrence for Diagnosis and Treatment of Breast Cancer, Shantou University Medical and development of breast cancer, further clarifying the College, Shantou 515041, China Full list of author information is available at the end of the article pathogenesis of breast cancer and providing a potential

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direction for further studies on the treatment of breast (PHGPx or GPx4) is found in the nucleus, cytosol, and cancers. mitochondria of various tissues. As an intracellular sele- nium protein, GPx4 can directly reduce the production The GPx family and its members of peroxide phospholipids in the cell membrane [16]. (5) GPxs are members of a multiple-isozyme family that cat- GPx6 is expressed in the olfactory epithelium of humans alyze the reduction of H­ 2O2 or organic hydroperoxides to and pigs [17]. However, GPx6 rarely has been studied, generate water or corresponding using reduced and its function has not been clearly defned. glutathione (GSH) as an electron donor [11]. Currently, 8 Among the three non- glutathione per- GPxs (GPx1–GPx8) have been identifed in mammalian oxidases, GPx5 is secreted from the epididymis and tissues, which exhibit the genetic, structural and dynamic is thought to protect sperm from peroxide-mediated diferences and perform common and separate functions attacks during maturation. Although the active domain [12] (Fig. 1). of GPx5 lacks , it retains prop- Among these GPxs, 5 selenium-dependent GPx erties [18]. Another non-selenium glutathione peroxi- isozymes have been identifed (Table 1). (1) Classical GPx dase, GPx7, which lacks GPx activity, has recently been (GPx1) is reported to be expressed in red blood cells and described as a novel phospholipid hydroperoxide GPx liver, lung, and kidney tissues and is located in the cyto- [11, 19–21]; the sequence of GPx7 encodes cysteine in its sol, nucleus, and mitochondria. Te antioxidant efects of conserved catalytic motifs [22]. As a non-selenocysteine, GPx1 are achieved by the direct reduction of hydrogen GPx8 is a membrane protein that is detected in the endo- peroxide and hydroperoxides [13]. (2) Gastrointes- plasmic reticulum, is present abundantly expressed in the tinal GPx (GPx2) is only found in the cytosol and nucleus lung, and was identifed as a novel member of the GPx of the gastrointestinal tract. Because of its specifc locali- family [23]. zation, GPx2 was the frst GPx considered to be a barrier In general, both the selenium-containing GPxs and to the absorption of hydrogen peroxide [14]. (3) Plasma non-selenium GPxs are key players in the biological envi- GPx (GPx3) is present in the mitochondria of several ronment and the development of human diseases [17]. organs, such as the kidney, lung, epididymis, breast, Te following section will describe the relationships and heart, and muscle. As the main antioxidant in molecular mechanisms of GPxs in disease development. plasma, GPx3 is the only extracellular enzyme in the GPx family that reduces ROS products during normal metab- ROS are the main molecules involved in the role olism or oxidative damage [15]. (4) Phospholipid GPx and mechanism of GPxs in the development of diseases ROS, reactive oxygen-containing molecules, are the nor- mal products of aerobic reactions in humans, such as oxidative respiration in mitochondria [24]. ROS are pro- duced by multiple intrinsic mechanisms, and ROS come in a variety of forms, including radical (hydroxyl, super- oxide, etc.) or non-radical (hydrogen peroxide, singlet oxygen, etc.) [25]. Te intrinsic level of ROS in the intra- cellular environment plays an important role in the main- tenance of cellular homeostasis in vivo; the level of ROS can be dramatically increased by external stimuli or inter- nal stresses and can be toxic to cells [26]. To neutralize ROS, systematic biological detoxifcation processes are used to maintain their normal level; for example, N-ace- tylcysteine (NAC) in preadipocytes reduces adipogenesis [27]. In organisms, two systems have been developed to neutralize these compounds, including non-enzymatic and enzymatic systems. In addition to superoxide dis- mutases, , and ascorbate peroxidases, GPxs are important components of the enzymatic systems and are the focus of this article [11] (Table 1). GPxs, which par- ticipate in the processes of antioxidant protection and detoxifcation, are important enzymes that directly regu- Fig. 1 The main distribution of GPxs in human late ROS levels [28]. Te group of GPx enzymes, which Zhang et al. J Transl Med (2020) 18:247 Page 3 of 11

Table 1 The types of GPxs and their proven substrates GPxs Types Expressions Locations Oxidizing Reducing Peroxidatic References substrates substrate residue

GPx1 Selenium-dependent Red cells, liver, lung, Cytosol, nucleus, H2O2, soluble low GSH Sec [17, 83] and kidney and mitochondria MM hydroper‑ oxides GPx2 Selenium-dependent Gastrointestinal Cytosol and nucleus N.F. N.F. Sec [118–120] tract

GPx3 Selenium-dependent Kidney, lung, Mitochondria H2O2, soluble low GSH, low rate with Sec [17, 121] epididymis, MM hydroper‑ thioredoxin and breast, heart, and oxides glutaredoxin muscle

GPx4 Selenium-dependent Various tissues Nucleus, cytosol, H2O2, small GSH, Dithiothreitol Sec [122–124] and mitochondria hydroperoxides, hydroperoxides in complex GPx5 Non-Selenium- Epididymis Extracellular N.F. N.F. Cys [17, 125] dependent GPx6 Selenium-dependent Olfactory epithe‑ N.A. N.F. N.F. Sec (human) [17, 126] in human lium Cys (rats)

GPx7 Non-Selenium- Preadipocytes N.A. H2O2 GSH, Protein Cys [17, 127, 128] dependent disulfde isomer‑ ase

GPx8 Non-Selenium- Lung Endoplasmic H2O2 GSH Cys [128, 129] dependent reticulum

MM molecular mass, N.F. not found, N. A. not available play an irreplaceable role in the regulation of ROS home- pathways; these functions suggest a role of ROS as signal- ostasis in vivo, has been thought to use GSH as a reduc- ing molecules that favor tumorigenesis. However, a high ing agent to catalyze the reduction of H­ 2O2 or organic level of ROS inhibits the occurrence and development of peroxides to generate water or corresponding alcohols, tumors by inducing apoptosis of tumor cells because of respectively [17]. their toxic efects [40]. Recently, research on tumor treat- It is accepted that an excessive burden of ROS may ment strategies has focused on whether the treatment lead to abnormal cell growth, corresponding changes in that opposes or promotes oxidation exert anti-tumor intracellular homeostasis and damage to important com- efects. Accumulated evidence suggests that ROS func- ponents of in the cell when the antioxidant defense and/ tion as second messengers in the determination of cell or DNA repair mechanisms cannot balance the excess fate and the modifcation of various signaling molecules oxidants [29]. , which results from the [41]. Terefore, the regulation of ROS homeostasis is imbalance between the production and neutralization of crucial for maintaining the health of humans. Te explo- ROS, is also reported to be involved in a large number of ration and investigation of GPxs, as key enzymes that pathological states, such as Alzheimer’s disease [30], Par- regulate ROS levels in humans, is of great signifcance kinson’s disease [31], atherosclerosis [32], heart failure to elucidate the relationship between GPxs and diseases, [33], myocardial infarction [34], and hepatic encepha- including tumors, to further understand the pathogenesis lopathy [35]. Importantly, oxidative damage caused by of diseases and to prevent ameliorate and even cure these the production of ROS has been linked to the etiology of diseases. diferent types of human cancer [23, 36]. Te diverse roles of GPxs in diferent kinds of tumors In the initial stage of carcinogenesis, ROS play a vari- have been examined but remain controversial. For exam- ety of roles, including mediating the activation of car- ple, GPx1 has been reported to prevent oxidative DNA cinogens, causing DNA damage, and interfering with mutations, which in turn may prevent the development responses to DNA damage [37–39]. Low levels of ROS of tumors [42], and research shows that overexpression can activate host cells in the tumor microenvironment, of GPx1 can reduce tumor growth, indicating its inhibi- and promote glucose metabolism in tumors to main- tory efect in tumorigenesis [43]. However, the expres- tain the high energy consumption of tumors by induc- sion of GPx1 has been reported to be down-regulated in ing mitochondrial autophagy, altering key enzymes and thyroid cancer [44], colorectal cancer [45, 46], and gas- related glucose metabolism and activating signal tric cancer [47], whereas GPx1 has been demonstrated Zhang et al. J Transl Med (2020) 18:247 Page 4 of 11

to play an oncogenic role in kidney cancer [48], pancre- profle and aquaporin expression under conditions of oxi- atic cancer [49], and laryngeal squamous cell carcinoma dative stress in diferent types of breast cancer cells and [50]. Te abnormal expression of GPx2 was detected in predicted the subsequent metabolic reprogramming of diferent tumors, and GPx2 was up-regulated in colo- cancer cells and adaption to stress and resistance to ther- rectal cancer [51, 52] and down-regulated in prostate apies [68]. intraepithelial neoplasia [53], suggesting that GPx2 plays Te development of drug resistance is a challenge for complex roles in tumorigenesis [23]. Currently, GPx3 is the use of adjuvant therapies in breast cancer patients considered a new tumor-suppressor [23], and its [69], and studies suggest that ROS may play an important hypermethylation, which is associated with the further role in the production of drug-resistant cells [70]. Zhong down-regulation of GPx3, was observed in patients with et al. demonstrated that oxidative stress and H­ 2O2 treat- Barrett’s esophagus [54], endometrial adenocarcinoma ment led to a marked increase in senescence-associated [55] and prostate cancer [56]. GPx4 is also considered a β-galactosidase activity but only to minimal apoptotic cell tumor suppressor because it is down-regulated in tumors death in CSCs, suggesting that ROS triggered the induc- [23, 43]. Current investigations have demonstrated that tion of senescence and exhibited therapeutic potential in GPx7 has potential tumor-suppressive efects in gastric the eradication of drug-resistant CSCs [8]. However, the and esophageal adenocarcinoma [57–59]. Due to limited increase in ROSs induced by drugs seems to play a difer- research, the roles of GPx5, GPx6, and GPx8 in tumori- ent role compared to the role of ROS originally generated genesis are still awaiting clarifcation. in malignant tumors. In the treatment of breast cancer, anti-estrogen tamoxifen, the drug most often used for the The role of ROS in the occurrence and development long-term treatment of early breast cancer, can induce of breast cancer apoptosis in many cells, and this efect may be mediated Te occurrence of breast cancer, the most common by ROS generation in the mitochondria of breast cancer malignancy in females worldwide, is generally believed cells [71]. to be signifcantly associated with the accumulation of genetic damage caused by genetic alterations, which The role of GPxs in breast cancer cause uncontrolled cell proliferation and/or abnormal As mentioned above, ROS is closely related to the programmed cell death, or apoptosis [60]. Excessive molecular mechanism of breast cancer progression, and burden of ROS, failure of clearance mechanisms and ROS can be directly regulated by GPxs, which eliminate even lack of may lead to the accumulation organic peroxides at the expense of GSH [10]. Te fol- of ROS and to oxidative stress [40], which are associated lowing section will illustrate the relationship between with genetic damage and breast cancer onset [61–65]. diferent GPxs and breast cancer and their underlying Sies et al. systematically reviewed the oxidative stress molecular mechanisms to provide opportunities for fur- from the perspectives of oxidants and antioxidants, and ther investigation and research and to beneft patients noted that oxidants with vastly diferent half-lives may with breast cancer (Table 2). be observed at the site of generation or be transported to distant target sites where they exert oxidant activities in GPx1 cell metabolism [63]. On the other hand, antioxidants can Te GPx1 gene, which encodes the frst identifed sele- protect the cells from incident radiation through special- noprotein, is located on 3p21 [72, 73]. ized pigments and control the levels of reactive species Previous research has shown that GPx1 is an efective which otherwise might cause a cascade of reactions and antioxidant enzyme that cannot be replaced by any other lead to the generation of pathological oxidants [63]. to protect against generalized oxidative Considering the molecular mechanism of ROS in the stress [74–76]. When cancerous cells are generated, the mammary gland, it appears that the oxidative state is expression of GPx1 is abnormal, causing intracellular involved in the initial occurrence and development of ROS dysfunction [77, 78]. Due to its antioxidant proper- breast cancer through interference with breast cancer ties, GPx1 is thought to be highly efective in preventing stem cells (CSCs) [66]. Malins et al. found that oxidative the ROS-mediated initiation of cancer. stress changed the potential of the breast, lead- In breast cancer, transcription factor AP-2 gamma ing to drastic changes in the DNA base lesions, which (TFAP2C) is an important transcription factor that regu- are conducive to oxidative conditions and breast cancer lates estrogen receptor-alpha (ERα) and c-ErbB2/HER2 formation [64]. Interestingly, a positive feedback loop (Her2), which are involved in the establishment of the between miR526b/655 and oxidative stress was identifed pattern observed in diferent clinical in breast cancer, and the loop promotes tumor growth phenotypes of breast cancer [79, 80]. Interestingly, Kulak and metastasis [67]. Rodrgues et al. analyzed the lipid et al. confrmed that TFAP2C regulated GPx1 expression Zhang et al. J Transl Med (2020) 18:247 Page 5 of 11

Table 2 The expression, function and potential mechanism of GPxs in breast cancers GPxs Location Main fndings in breast cancers References

GPx1 3p21.31 TFAP2C regulates GPx1 promoter through an AP-2 regulatory region [81] GPx1 polymorphism in modifying stress response [82] Decreased GPx1 expression [83] Loss of heterozygosity and allelic diferences of GPx1 [88] Pro198Leu-associated decreased GPx1 activity with high breast cancer risk [89, 92] The Leu198Leu genotype of GPx-1 [91] Regulate the sensitivity to doxorubicin [93] GPx2 14q23.3 Upregulated in breast cancer cells [19] Overexpression in rat breast cancer [98] Highly regulated by retinoic acid [94] GPx3 5q33.1 Downregulated in aggressive phenotype of breast cancer [103] An independent predictive marker for local recurrence of early-stage invasive cancer [104] patients GPx4 19p13.3 Downregulated in breast cancer cells [19] Predict poor prognosis of invasive ductal breast carcinoma [106] Impaired GPx4 expression in peripheral blood monocytes as a biomarker for increased [111] breast cancer risk GPx5 6p22.1 Downregulated in breast cancer cells [19] GPx6 6p22.1 Downregulated in breast cancer cells [19] GPx7 1p32.3 Downregulated in breast cancer cells [19] GPx8 5q11.2 Not available

by directly binding to the GPx1 promoter, which contains Hence, due to the controversial evidence, exploring an AP-2 regulatory region, and the methylation of the the molecular regulation of GPx1 expression and activity CpG island in the GPx1 promoter region prevented the is very important for understanding the mechanisms of binding of TFAP2C by encompassing the AP-2 regula- cancers. Frequent loss of heterozygosity (LOH) on chro- tory region [81]. As expected, compared to those healthy mosome 3p in lung tumors was associated with low GPx1 control subjects, the tissues of breast cancer patients enzyme activities, which may afect the prognosis of lung exhibit signifcantly increased lipid peroxidation, which cancer patients [86]. Moscow et al. frst reported a poly- is dependent on functional polymorphism of GPx1 [82]. morphism in GPx1, namely, a substitution at codon 198 However, compared to that in non-malignant tissues, of either proline (Pro) or leucine (Leu), Pro198Leu (SNP: the expression level of GPx1 in tumor tissues was signif- 1050450), in lung cancer [87]. In a Macedonian popula- cantly decreased by 7.4% [83]. tion, the GPx1 Pro198Leu genotype showed an overall Te controversial expression pattern of GPx1 in breast protective efect on prostate cancer risk, and erythrocyte cancers requires further investigation to determine its GPx1 activities were signifcantly decreased in prostate molecular functions. Artifcial overexpression of GPx1 cancer patients compared with controls [73]. Similarly, showed an increased capacity to rescue breast cancer in breast cancer, LOH at this occurred in approxi- cells from the cell cycle arrest caused by hyperoxic stress, mately 36% of breast cancer tissues, and GPx1 with a indicating the involvement of both peroxide-derived free leucine-containing exhibited lower GPx1 activities radicals and nonperoxide-derived species during the del- in response to stimulation than GPx1 a proline-contain- eterious process [84]. Gouaze et al. found that increased ing allele [88]. Ravn-Haren et al. showed similar results, GPx1 levels signifcantly increased the resistance of namely, that Pro198Leu-associated GPx1 activities were breast cancer T47D cells to doxorubicin partially by decreased in breast cancer but were associated with interfering with the activation of the sphingomyelin-cer- increased breast cancer risk among Danish females [89]. amide pathway [85]. Although such research is limited, In addition to the Leu198Leu genotype in the GPx1 gene, the overexpression of GPx1 in breast cancer is thought the Ala16Ala genotype in the manganese superoxide dis- to promote the occurrence and development of breast mutase (MnSOD) gene, the most signifcant enzyme that cancer. protects against ROS in the human body [90], was also Zhang et al. J Transl Med (2020) 18:247 Page 6 of 11

associated with an increased risk of breast cancer [91]. It with its up-regulation in human breast cancer [19]. As is suggested that Leu carriers with the Pro198Leu GPx1 expected, the inhibition of GPx2 expression by siRNA led allele had a 1.9-fold increased risk of non-ductal breast to signifcant growth inhibition in both rat and human cancer and a 2.6-fold increased risk of developing grade 3 breast cancer cell lines [19, 98]. Chu et al. confrmed ductal tumors [92]. Tese results indicated that the Pro- that in MCF-7 cells, which a low aggressive breast can- 198Leu polymorphism in GPx1 and the associated LOH cer cell line, the expression of GPx2 can be substantially are factors of signifcance in breast cancer development. up-regulated by retinoic acid [94]. Due to its potential Regarding treatment strategies, it is suggested that the function in the occurrence and development of breast marked decrease in GPx1 expression may be the major cancer, GPx2 is suggested as a potential target for the mechanism of tumor sensitization to anthracyclines [93] prevention and treatment of breast cancer. However, the and that GPx1 can partially inhibit doxorubicin-induced current research on the relationship between GPx2 and cell death-related signaling in breast cancer by interfering breast cancer is limited and there are still many gaps in with the activation of the sphingomyelin-ceramide path- the research regarding its regulatory mechanisms. way [85]; these fndings suggest that tumor regression in response to chemotherapy was correlated with the inhi- GPx3 bition of GPx1 activity and confrmed the role of GPx1 in As mentioned above, elevated levels of ROS play a crucial the occurrence and development of breast cancer (Fig. 2). role in the progression of breast cancer [99]. As the only extracellular enzyme in the GPx family, GPx3 is an essen- GPx2 tial enzyme that is responsible for removing ROS prod- Te selenium-dependent GPx-GI ucts during normal metabolism or oxidative damage in encoded by GPx2 is highly expressed in gastrointesti- healthy tissues [76]. Lee et al. observed a high frequency nal epithelial cells and occasionally in breast tissue [94]. of promoter hypermethylation and progressive loss of In addition to normal tissues, it has been reported that GPx3 expression in Barrett’s esophagus and its associ- GPx2 is upregulated in a variety of tumor cells [76, 95] ated lesions, and these authors also confrmed the known and is associated with tumor cell proliferation and poor function of GPx3 as a potent antioxidant [54]. In human prognosis of patients [96, 97]. thyroid cancer, GPx3 is frequently methylated, and the In breast cancer, GPx2 is commonly overexpressed in expression of GPx3 is regulated by methylation of the the mammary carcinomas of mouse models of breast promoter region, and this methylation is related to tumor cancer induced by carcinogens, which is consistent size and lymph node metastasis through the inhibition

Fig. 2 The reported function and mechanism of GPx1. TFAP2C transcription factor AP-2 gamma, AP-2 AP-2 regulatory region, LOH loss of heterozygosity, Dox doxorubicin Zhang et al. J Transl Med (2020) 18:247 Page 7 of 11

of Wnt/β-catenin signaling [100]. Te methylation of the and MDA-MB-231 cell lines and GPx6 was also down- GPx3 promoter was also observed in hepatocellular car- regulated in MDA-MB-231cells compared with healthy cinoma (HCC) tissue [101] and gastric carcinoma [102], breast MCF-10A cells [19]. However, relevant research possibly leading to subsequent carcinogenesis and cancer on their roles in breast cancer and the regulatory mecha- cell progression. Tese fndings suggest that epigenetic nisms are still lacking and needs to be supplemented. Te inactivation and regulation of the GPx3 pathway may be expression pattern and function of GPx8 in breast cancer critical in the development and progression of diferent have not been reported. types of cancers. Consistently, the GPx3 levels were reported to be Therapeutic implications down-regulated in aggressive infammatory breast cancer Based on the role of ROS in breast cancer, several rea- (IBC) carcinoma tissues compared to non-IBC tissues, gents have been reported to be potential therapeutic and this down-regulation was associated with hyper- methods for patients with breast cancer. Methanolic methylation of the GPx3 promoter [103]. In addition, a extract of corn silk, which induces apoptosis in breast low level of GPx3 is an independent predictive marker of cancer cells was proposed to be a novel anti-tumor agent the local recurrence of early-stage invasive breast cancer that acts by increasing ROS production and decreasing in patients undergoing breast-conserving surgery and GSH levels in a dose-dependent manner [112]. De et al. radiotherapy, regardless of the patient’s clinicopatho- reported the therapeutic potential of another natural logical parameters [104]; this observation suggests that quinazoline derivative that promoted oxidative stress and inactivation of the GPx3 gene by hypermethylation of the increased ROS production [113]. George et al. proposed promoter may contribute to breast cancer progression. Rubus bioactive compounds as another reagent to induce apoptotic cell death in human breast cancer cells [114]. In GPx4 triple-negative breast cancer (TNBC) cells treated with GPx4 was discovered in 1982 by Ursini et al. [105], and isorhamnetin (IH) and chloroquine (CQ), ROS induced GPx4 is the only known enzyme able to reduce lipid Drp1-dependent mitochondrial fssion and apoptosis by peroxides bound to cell membranes [106, 107]. In con- mediating the activation and mitochondrial translocation trast to other GPxs, GPx4 is the only one that reduces of CaMKII; this study suggested IH as a novel chemo- the hydroperoxides of lipoproteins and complex lipids, therapeutic agent [115]. such as cholesterol, cholesterol esters, and phospholipids As an important group of antioxidative enzymes, the [108], to protect mitochondrial ATP generation from oxi- normal levels of GPxs help to control the level of reac- dative damage [109]. Recently, GPx4 was predicted to be tive species. Te identifcation of ways to improve the a specifc target for new pharmacological therapies aimed expression of GPxs in malignant tumors, especially in at activating or inhibiting cell death in cancer or degen- breast cancers, is further research direction. However, erative diseases [110]. to date, the methods used to increase GPx expres- Interestingly, GPx4 expression was down-regulated in sion are mainly the artifcial over-expression of GPxs breast cancer cells compared with normal breast cells through transfections or infections. After confrming [19]. A recent study showed a strong negative correla- the clinical signifcance and potential therapeutic role tion between breast tumor grade progression and GPx4 of GPx3 in tumor recurrence after liver transplantation expression in breast cancer tissues, and its downregula- [116], Qi et al. constructed and verifed a delivery sys- tion may be related to the poor prognosis of patients with tem by composed of mesenchymal stem cells derived invasive ductal carcinoma of the breast [106]. In addition, from human induced pluripotent stem cells (hiPSC- impaired GPx4 expression in peripheral blood mono- MSCs) to increase the expression level of GPx3 in vivo cytes was shown to be a biomarker of increased risk of [117]. Te engineered hiPSC-MSCs successfully deliv- breast cancer [111]. However, the specifc mechanism ered GPx3 to the liver and ameliorated hepatic injury of GPx4 in the occurrence of breast cancer has not been by inhibiting hepatic senescence [117]; this result pro- elucidated and requires further study. vides potential therapeutic strategies and prospects for breast cancer treatment. Based on the review of Other GPxs key role of ROS in the occurrence and development of As studies of the functions of GPx5, GPx6 and GPx7 in breast cancer, it is inspired that the changed expres- the development of breast cancer are limited, it is dif- sion level of GPxs may achieve the therapeutic pur- cult to determine their underlying mechanisms. Rusolo pose after determining its clinical signifcance in breast et al. systemically examined the expression of GPxs in cancer. For example, the inactivation of GPx3 may breast cancer cell lines and found that GPx5 and GPx7 contribute to the progression of breast cancer [103, were down-regulated in the human breast cancer MCF-7 104]. So the delivery of GPx3 to breast tumor tissues Zhang et al. J Transl Med (2020) 18:247 Page 8 of 11

through hiPSC-MSCs or other methods may promote Availability of data and materials Not applicable. its expression, and reduce the infuence of ROS on the progression of breast cancer accordingly, fnally achieve Ethics approval and consent to participate the goal of treating breast cancer. Although there is no Not applicable. corresponding research report at present, this method Consent for publication undoubtedly provides a new idea and strategy for the Not applicable. treatment of breast cancer. Competing interests The authors declare that they have no competing interests.

Conclusion Author details 1 Changjiang Scholar’s Laboratory/Guangdong Provincial Key Laboratory Breast cancer is a serious threat to the health of women for Diagnosis and Treatment of Breast Cancer, Shantou University Medical around the world, and the mechanism of its occurrence College, Shantou 515041, China. 2 Department of General Surgery, the First and treatment is of great signifcance. Te identifcation Afliated Hospital of Shantou University Medical College, Shantou 515041, China. 3 Department of Physiology/Cancer Research Center, Shantou Univer‑ of the relationship between GPxs and breast cancer is sity Medical College, Shantou 515041, China. 4 Department of Hematology, valuable for the discovery of potential therapeutic tar- the First Afliated Hospital of Shantou University Medical College, Shantou, gets for breast cancer. A greater understanding of the People’s Republic of China. pathogenesis of breast cancer will increase the chances Received: 17 March 2020 Accepted: 17 June 2020 of identifying a cure. At present, there has been substan- tial research on the relationship between GPxs and breast cancer, but the research is still very limited. Tis review provides a systematic and clear summary of the relation- References ship between GPxs and breast cancer to elucidate the 1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and role of GPxs in the pathogenesis of breast cancer and to mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. provide a clear direction. Tere is a large gap waiting to 2018;68:394–424. be flled by subsequent researchers to yield better thera- 2. Ono M, Ogilvie JM, Wilson JS, Green HJ, Chambers SK, Ownsworth T, Shum DH. 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All authors read of glutathione peroxidase (GPx) in the ROS signaling pathway, hyphal and approved the fnal manscript. branching and the regulation of ganoderic acid biosynthesis in Gano‑ derma lucidum. Fungal Genet Biol. 2015;82:168–80. Funding 11. Margis R, Dunand C, Teixeira FK, Margis-Pinheiro M. Glutathione peroxi‑ This work was supported by the National Natural Science Foundation of China dase family—an evolutionary overview. FEBS J. 2008;275:3959–70. (Nos. 81501539), the Natural Science Foundation of Guangdong Province 12. Brown KM, Pickard K, Nicol F, Beckett GJ, Duthie GG, Arthur JR. Efects (No. 2016A030312008), the Li Ka Shing Foundation Grant for Joint Research of organic and inorganic selenium supplementation on selenoenzyme Program between Shantou University and Technion-Israel Institute of Technol‑ activity in blood lymphocytes, granulocytes, platelets and erythrocytes. ogy (No. 43209501), and “Dengfeng Project” for the construction of high-level Clin Sci. 2000;98:593–9. hospitals in Guangdong Province–the First Afliated Hospital of Shantou 13. Rotruck JT, Pope AL, Ganther HE, Swanson AB, Hafeman DG, Hoekstra University Medical College Supporting Funding (No. 202003-10). WG. Selenium: biochemical role as a component of glutathione peroxi‑ dase. Science. 1973;179:588–90. Zhang et al. J Transl Med (2020) 18:247 Page 9 of 11

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