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Volume 28, Issue 1
  • ISSN: 1386-2073
  • E-ISSN: 1875-5402

Abstract

Background and Purpose

FuZheng YiLiu Formula (FZYL) is a commonly used formula for postoperative estrogen receptor-positive (ER+) breast cancer and post-radiotherapy deficiency of both Qi and Yin. FZYL has been used in clinical practice for decades because of its ability to effectively improve the symptoms of deficiency in cancer patients. However, its mechanism needs to be further clarified. In this paper, we will observe the effect of FZYL on mice with ER+ breast cancer and explore the mechanism by which it improves the symptoms of ER+ breast cancer.

Materials and Methods

A tumor xenograft mouse model was established to detect tumor growth in order to evaluate the pharmacological effects of FZYL on ER+ breast cancer. The main targets of FZYL were identified by extracting the FZYL components and the corresponding potential target genes of breast cancer from the established database and constructing a protein-protein interaction network of shared genes using the string database. GO functional annotation and KEGG pathway enrichment analysis were performed, and molecular docking, molecular dynamics simulations, western blotting analysis, and RT-qPCR were performed to confirm the validity of targets in the relevant pathways.

Results

FZYL was able to significantly reduce the size of tumors and had a significant therapeutic effect on tumor xenograft mice. GO and KEGG pathway enrichment analyses indicated that the effects of FZYL may be mediated by oxidative stress levels, apoptotic signaling pathways, and cell cycle proliferation. By RT-qPCR and protein blotting assays, FZYL targeted the key targets of TP53, JUN, ESR1, RELA, MYC, and MAPK1 to exert its effects. The key active components of FZYL are quercetin, luteolin, stigmasterol, and glycitein. Molecular docking and molecular dynamics simulation results further demonstrated that the key active components of FZYL are stably bound to the core targets.

Conclusion

In this study, the potential active ingredients, potential core targets, key biological pathways, and signaling pathways involved in the treatment of breast cancer with FZYL were identified, providing a theoretical basis for further anti ER+ breast cancer research.

© 2025 Bentham Science Publishers
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2023-11-10
2025-01-31

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References

  1. SungH. FerlayJ. SiegelR.L. LaversanneM. SoerjomataramI. JemalA. BrayF. Global cancer statistics 2020: GLOBOCAN Estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J. Clin.202171320924910.3322/caac.21660 33538338
     [Google Scholar]
  2. ByrneK. LevinsK.J. BuggyD.J. Can anesthetic-analgesic technique during primary cancer surgery affect recurrence or metastasis?Can. J. Anaesth.201663218419210.1007/s12630‑015‑0523‑8 26497721
     [Google Scholar]
  3. BrittK.L. CuzickJ. PhillipsK.A. Key steps for effective breast cancer prevention.Nat. Rev. Cancer202020841743610.1038/s41568‑020‑0266‑x 32528185
     [Google Scholar]
  4. BigaardJ. StahlbergC. JensenM.B. EwertzM. KromanN. Breast cancer incidence by estrogen receptor status in Denmark from 1996 to 2007.Breast Cancer Res. Treat.2012136255956410.1007/s10549‑012‑2269‑0 23053655
     [Google Scholar]
  5. KawiakA. Molecular research and treatment of breast cancer.Int. J. Mol. Sci.20222317961710.3390/ijms23179617 36077013
     [Google Scholar]
  6. HuppertL.A. MariottiV. ChienA.J. SolimanH.H. Emerging immunotherapeutic strategies for the treatment of breast cancer.Breast Cancer Res. Treat.2022191224325510.1007/s10549‑021‑06406‑1 34716870
     [Google Scholar]
  7. WangY. MindenA. Current molecular combination therapies used for the treatment of breast cancer.Int. J. Mol. Sci.202223191104610.3390/ijms231911046 36232349
     [Google Scholar]
  8. TeitenM.H. DicatoM. DiederichM. Hybrid curcumin compounds: a new strategy for cancer treatment.Molecules20141912208392086310.3390/molecules191220839 25514225
     [Google Scholar]
  9. JiangM. ShengF. ZhangZ. MaX. GaoT. FuC. LiP. Andrographis paniculata (Burm.f.) Nees and its major constituent andrographolide as potential antiviral agents.J. Ethnopharmacol.202127211395410.1016/j.jep.2021.113954 33610706
     [Google Scholar]
  10. JiangM. ZhaoS. YangS. LinX. HeX. WeiX. SongQ. LiR. FuC. ZhangJ. ZhangZ. An “essential herbal medicine”—licorice: A review of phytochemicals and its effects in combination preparations.J. Ethnopharmacol.202024911243910.1016/j.jep.2019.112439 31811935
     [Google Scholar]
  11. ZhangX. QiuH. LiC. CaiP. QiF. The positive role of traditional Chinese medicine as an adjunctive therapy for cancer.Biosci. Trends202115528329810.5582/bst.2021.01318 34421064
     [Google Scholar]
  12. ZhangY. LouY. WangJ. YuC. ShenW. Research status and molecular mechanism of the traditional Chinese medicine and anti-tumor therapy combined strategy based on tumor microenvironment.Front. Immunol.20211160970510.3389/fimmu.2020.609705 33552068
     [Google Scholar]
  13. YangZ. ZhangQ. YuL. ZhuJ. CaoY. GaoX. The signaling pathways and targets of traditional Chinese medicine and natural medicine in triple-negative breast cancer.J. Ethnopharmacol.202126411324910.1016/j.jep.2020.113249 32810619
     [Google Scholar]
  14. QiF. ZhaoL. ZhouA. ZhangB. LiA. WangZ. HanJ. The advantages of using traditional Chinese medicine as an adjunctive therapy in the whole course of cancer treatment instead of only terminal stage of cancer.Biosci. Trends201591163410.5582/bst.2015.01019 25787906
     [Google Scholar]
  15. XiaoY. LiuY. LaiZ. HuangJ. LiC. ZhangY. GongX. DengJ. YeX. LiX. An integrated network pharmacology and transcriptomic method to explore the mechanism of the total Rhizoma Coptidis alkaloids in improving diabetic nephropathy.J. Ethnopharmacol.202127011380610.1016/j.jep.2021.113806 33444721
     [Google Scholar]
  16. ZhangR. ZhuX. BaiH. NingK. Network pharmacology databases for traditional chinese medicine: Review and assessment.Front. Pharmacol.20191012310.3389/fphar.2019.00123 30846939
     [Google Scholar]
  17. NogalesC. MamdouhZ.M. ListM. KielC. CasasA.I. SchmidtH.H.H.W. Network pharmacology: curing causal mechanisms instead of treating symptoms.Trends Pharmacol. Sci.202243213615010.1016/j.tips.2021.11.004 34895945
     [Google Scholar]
  18. HanH. FengX. GuoY. ChengM. CuiZ. GuoS. ZhouW. Identification of potential target genes of breast cancer in response to Chidamide treatment.Front. Mol. Biosci.2022999958210.3389/fmolb.2022.999582 36425653
     [Google Scholar]
  19. RuJ. LiP. WangJ. ZhouW. LiB. HuangC. LiP. GuoZ. TaoW. YangY. XuX. LiY. WangY. YangL. TCMSP: a database of systems pharmacology for drug discovery from herbal medicines.J. Cheminform.2014611310.1186/1758‑2946‑6‑13 24735618
     [Google Scholar]
  20. YanD. ZhengG. WangC. ChenZ. MaoT. GaoJ. YanY. ChenX. JiX. YuJ. MoS. WenH. HanW. ZhouM. WangY. WangJ. TangK. CaoZ. HIT 2.0: an enhanced platform for Herbal Ingredients’.Targets. Nucleic Acids Res.202250D1D1238D124310.1093/nar/gkab1011 34986599
     [Google Scholar]
  21. TsaiS.Y.A. PokrassM.J. KlauerN.R. NoharaH. SuT.P. Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid.Proc. Natl. Acad. Sci. USA2015112216742674710.1073/pnas.1422001112 25964330
     [Google Scholar]
  22. RappaportN. TwikM. PlaschkesI. NudelR. Iny SteinT. LevittJ. GershoniM. MorreyC.P. SafranM. LancetD. MalaCards: an amalgamated human disease compendium with diverse clinical and genetic annotation and structured search.Nucleic Acids Res.201745D1D877D88710.1093/nar/gkw1012 27899610
     [Google Scholar]
  23. YuJ. ZhouY. TanakaI. YaoM. Roll: a new algorithm for the detection of protein pockets and cavities with a rolling probe sphere.Bioinformatics2010261465210.1093/bioinformatics/btp599 19846440
     [Google Scholar]
  24. TrapaniD. GinsburgO. FadeluT. LinN.U. HassettM. IlbawiA.M. AndersonB.O. CuriglianoG. Global challenges and policy solutions in breast cancer control.Cancer Treat. Rev.202210410233910.1016/j.ctrv.2022.102339 35074727
     [Google Scholar]
  25. LeeY.W. ChenT.L. ShihY.R.V. TsaiC.L. ChangC.C. LiangH.H. TsengS.H. ChienS.C. WangC.C. Adjunctive traditional Chinese medicine therapy improves survival in patients with advanced breast cancer: A population-based study.Cancer201412091338134410.1002/cncr.28579 24496917
     [Google Scholar]
  26. ChenW. BaiH. LiuL. ChenH. ShiQ. ChangL. GouX. QianJ. Fuzheng Yiliu Formula Regulates Tumor Invasion and Metastasis through Inhibition of WAVE3 Expression.Evid. Based Complement. Alternat. Med.2021202111410.1155/2021/8898668 33854560
     [Google Scholar]
  27. LeeH.J. SeoN.J. JeongS.J. ParkY. JungD.B. KohW. LeeH.J. LeeE.O. AhnK.S. AhnK.S. LüJ. KimS.H. Oral administration of penta-O-galloyl- -D-glucose suppresses triple-negative breast cancer xenograft growth and metastasis in strong association with JAK1-STAT3 inhibition.Carcinogenesis201132680481110.1093/carcin/bgr015 21289371
     [Google Scholar]
  28. GanesanK. DuB. ChenJ. Effects and mechanisms of dietary bioactive compounds on breast cancer prevention.Pharmacol. Res.202217810597410.1016/j.phrs.2021.105974 34818569
     [Google Scholar]
  29. LathamS.L. O’DonnellY.E.I. CroucherD.R. Non-kinase targeting of oncogenic c-Jun N-terminal kinase (JNK) signaling: the future of clinically viable cancer treatments.Biochem. Soc. Trans.20225061823183610.1042/BST20220808 36454622
     [Google Scholar]
  30. JiangD. SongY. CaoW. WangX. JiangD. LvZ. YangZ. LiF. p53-independent role of MYC mutant T58A in the proliferation and apoptosis of breast cancer cells.Oncol. Lett.201917110711079 30655867
     [Google Scholar]
  31. HaganM. ManderS. JosephC. McGrathM. BarrettA. LewisA. HillW. BrowningD. McGee-LawrenceM. CaiH. LiuK. BarrettJ. GewirtzD. ThangarajuM. SchoenleinP. Upregulation of the EGFR/MEK1/MAPK1/2 signaling axis as a mechanism of resistance to antiestrogen induced BimEL dependent apoptosis in ER + breast cancer cells.Int. J. Oncol.20226222010.3892/ijo.2022.5468 36524361
     [Google Scholar]
  32. Gurer-OrhanH. InceE. KonyarD. SasoL. SuzenS. The role of oxidative stress modulators in breast cancer.Curr. Med. Chem.201825334084410110.2174/0929867324666170711114336 28699501
     [Google Scholar]
  33. GuptaS.C. HeviaD. PatchvaS. ParkB. KohW. AggarwalB.B. Upsides and downsides of reactive oxygen species for cancer: the roles of reactive oxygen species in tumorigenesis, prevention, and therapy.Antioxid. Redox Signal.201216111295132210.1089/ars.2011.4414 22117137
     [Google Scholar]
  34. CaoJ. LiuX. YangY. WeiB. LiQ. MaoG. HeY. LiY. ZhengL. ZhangQ. LiJ. WangL. QiC. Decylubiquinone suppresses breast cancer growth and metastasis by inhibiting angiogenesis via the ROS/p53/BAI1 signaling pathway.Angiogenesis202023332533810.1007/s10456‑020‑09707‑z 32020421
     [Google Scholar]
  35. ZhangQ.X. BorgA. WolfD.M. OesterreichS. FuquaS.A. An estrogen receptor mutant with strong hormone-independent activity from a metastatic breast cancer.Cancer Res.199757712441249 9102207
     [Google Scholar]
  36. HuangB. OmotoY. IwaseH. YamashitaH. ToyamaT. CoombesR.C. FilipovicA. WarnerM. GustafssonJ.Å. Differential expression of estrogen receptor α, β1, and β2 in lobular and ductal breast cancer.Proc. Natl. Acad. Sci. USA201411151933193810.1073/pnas.1323719111 24449868
     [Google Scholar]
  37. VleugelM.M. GreijerA.E. BosR. van der WallE. van DiestP.J. c-Jun activation is associated with proliferation and angiogenesis in invasive breast cancer.Hum. Pathol.200637666867410.1016/j.humpath.2006.01.022 16733206
     [Google Scholar]
  38. ZhangY. PuX. ShiM. ChenL. QianL. SongY. YuanG. ZhangH. YuM. HuM. ShenB. GuoN. c-Jun, a crucial molecule in metastasis of breast cancer and potential target for biotherapy.Oncol. Rep.20071851207121210.3892/or.18.5.1207 17914574
     [Google Scholar]
  39. SmithL.M. WiseS.C. HendricksD.T. SabichiA.L. BosT. ReddyP. BrownP.H. BirrerM.J. cJun overexpression in MCF-7 breast cancer cells produces a tumorigenic, invasive and hormone resistant phenotype.Oncogene199918446063607010.1038/sj.onc.1202989 10557095
     [Google Scholar]
  40. HeH. SinhaI. FanR. HaldosenL.A. YanF. ZhaoC. Dahlman-WrightK. c-Jun/AP-1 overexpression reprograms ERα signaling related to tamoxifen response in ERα-positive breast cancer.Oncogene201837192586260010.1038/s41388‑018‑0165‑8 29467493
     [Google Scholar]
  41. DhanasekaranD.N. ReddyE.P. JNK-signaling: A multiplexing hub in programmed cell death.Genes Cancer201789-1068269410.18632/genesandcancer.155 29234486
     [Google Scholar]
  42. WuQ. WuW. JacevicV. FrancaT.C.C. WangX. KucaK. Selective inhibitors for JNK signalling: a potential targeted therapy in cancer.J. Enzyme Inhib. Med. Chem.202035157458310.1080/14756366.2020.1720013 31994958
     [Google Scholar]
  43. LiT. KonN. JiangL. TanM. LudwigT. ZhaoY. BaerR. GuW. Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence.Cell201214961269128310.1016/j.cell.2012.04.026 22682249
     [Google Scholar]
  44. KastenhuberE.R. LoweS.W. Putting p53 in Context.Cell201717061062107810.1016/j.cell.2017.08.028 28886379
     [Google Scholar]
  45. ShiY. WuY. LiF. ZhangY. HuaC. YangJ. ZhengJ. ChenL. WeiZ. YueH. SunC. ZhouX. LiuS. Identifying the anti-metastasis effect of Anhydroicaritin on breast cancer: Coupling network pharmacology with experimental validation.J. Ethnopharmacol.202229311532610.1016/j.jep.2022.115326 35489659
     [Google Scholar]
  46. FridmanJ.S. LoweS.W. Control of apoptosis by p53.Oncogene200322569030904010.1038/sj.onc.1207116 14663481
     [Google Scholar]
  47. SantoroA. VlachouT. LuziL. MelloniG. MazzarellaL. D’EliaE. AobuliX. PasiC.E. ReavieL. BonettiP. PunziS. CasoliL. SabòA. MoroniM.C. DellinoG.I. AmatiB. NicassioF. LanfranconeL. PelicciP.G. p53 Loss in breast cancer leads to myc activation, increased cell plasticity, and expression of a mitotic signature with prognostic value.Cell Rep.2019263624638.e810.1016/j.celrep.2018.12.071 30650356
     [Google Scholar]
  48. HartlebenG. MüllerC. KrämerA. SchimmelH. ZidekL.M. DornblutC. WinklerR. EichwaldS. KortmanG. KosanC. KluiverJ. PetersenI. van den BergA. WangZ.Q. CalkhovenC.F. Tuberous sclerosis complex is required for tumor maintenance in MYC‐driven Burkitt’s lymphoma.EMBO J.20183721e9858910.15252/embj.201798589 30237309
     [Google Scholar]
  49. FallahY. BrundageJ. AllegakoenP. Shajahan-HaqA.N. MYC-driven pathways in breast cancer subtypes.Biomolecules2017745310.3390/biom7030053 28696357
     [Google Scholar]
  50. KřížováL. DadákováK. KašparovskáJ. KašparovskýT. Isoflavones.Molecules2019246107610.3390/molecules24061076 30893792
     [Google Scholar]
  51. ZhuY. YaoY. ShiZ. EveraertN. RenG. Synergistic effect of bioactive anticarcinogens from soybean on anti-proliferative activity in MDA-MB-231 and MCF-7 human breast cancer cells in vitro.Molecules2018237155710.3390/molecules23071557 29954123
     [Google Scholar]
  52. MageeP. McGlynnH. RowlandI. Differential effects of isoflavones and lignans on invasiveness of MDA-MB-231 breast cancer cells in vitro.Cancer Lett.20042081354110.1016/j.canlet.2003.11.012 15105043
     [Google Scholar]
  53. WenS. HeL. ZhongZ. ZhaoR. WengS. MiH. LiuF. Stigmasterol restores the balance of Treg/Th17 cells by activating the butyrate-PPARγ axis in colitis.Front. Immunol.20211274193410.3389/fimmu.2021.741934 34691046
     [Google Scholar]
  54. LiaoH. ZhuD. BaiM. ChenH. YanS. YuJ. ZhuH. ZhengW. FanG. Stigmasterol sensitizes endometrial cancer cells to chemotherapy by repressing Nrf2 signal pathway.Cancer Cell Int.202020148010.1186/s12935‑020‑01470‑x 33041661
     [Google Scholar]
  55. BakrimS. BenkhairaN. BouraisI. BenaliT. LeeL.H. El OmariN. SheikhR.A. GohK.W. MingL.C. BouyahyaA. Health benefits and pharmacological properties of stigmasterol.Antioxidants20221110191210.3390/antiox11101912 36290632
     [Google Scholar]
  56. MahaE.O.G.A-A.M.H. The anti-tumor effect of stigmasterol on sorafenib treated human breast cancer cell lines.Research Square2021
     [Google Scholar]
  57. FarshoriN.N. Al-OqailM.M. Al-SheddiE.S. Al-MassaraniS.M. AlamP. SiddiquiM.A. AhmadJ. Al-KhedhairyA.A. HPTLC estimation and anticancer potential of Aloe perryi petroleum ether extract (APPeE): A mechanistic study on human breast cancer cells (MDA-MB-231).J. King Saud Univ. Sci.202234410196810.1016/j.jksus.2022.101968
     [Google Scholar]
  58. QiuD. YanX. XiaoX. ZhangG. WangY. CaoJ. MaR. HongS. MaM. To explore immune synergistic function of Quercetin in inhibiting breast cancer cells.Cancer Cell Int.202121163210.1186/s12935‑021‑02345‑5 34838003
     [Google Scholar]
  59. KhorsandiL. OrazizadehM. NiazvandF. AbbaspourM.R. MansouriE. KhodadadiA. Quercetin induces apoptosis and necroptosis in MCF-7 breast cancer cells.Bratisl. Med. J.2017118212312810.4149/BLL_2017_025 28814095
     [Google Scholar]
  60. WuQ. NeedsP.W. LuY. KroonP.A. RenD. YangX. Different antitumor effects of quercetin, quercetin-3′-sulfate and quercetin-3-glucuronide in human breast cancer MCF-7 cells.Food Funct.2018931736174610.1039/C7FO01964E 29497723
     [Google Scholar]
  61. ImranM. RaufA. Abu-IzneidT. NadeemM. ShariatiM.A. KhanI.A. ImranA. OrhanI.E. RizwanM. AtifM. GondalT.A. MubarakM.S. Luteolin, a flavonoid, as an anticancer agent: A review.Biomed. Pharmacother.201911210861210.1016/j.biopha.2019.108612 30798142
     [Google Scholar]
  62. ShihY.L. LiuH.C. ChenC.S. HsuC.H. PanM.H. ChangH.W. ChangC.H. ChenF.C. HoC.T. YangY.Y. HoY.S. Combination treatment with luteolin and quercetin enhances antiproliferative effects in nicotine-treated MDA-MB-231 cells by down-regulating nicotinic acetylcholine receptors.J. Agric. Food Chem.201058123524110.1021/jf9031684 19921817
     [Google Scholar]
  63. ChenK.C. HsuW.H. HoJ.Y. LinC.W. ChuC.Y. KandaswamiC.C. LeeM.T. ChengC.H. Flavonoids Luteolin and Quercetin Inhibit RPS19 and contributes to metastasis of cancer cells through c-Myc reduction.Yao Wu Shi Pin Fen Xi201826311801191 29976410
     [Google Scholar]
  64. SunZ. ZhangsunM. DongS. LiuY. QianJ. ZhangsunD. LuoS. Differential expression of nicotine acetylcholine receptors associates with human breast cancer and mediates antitumor activity of αO-conotoxin GeXIVA.Mar. Drugs20201816110.3390/md18010061
     [Google Scholar]
/content/journals/cchts/10.2174/0113862073255044231027061742
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Integrating Network Pharmacology and In vivo Experimental Validation to Reveal the Mechanism of FuZheng YiLiu Formula on Estrogen Receptor Positive Breast Cancer
Comb Chem High Throughput Screen 28, 49 (2025); https://doi.org/10.2174/0113862073255044231027061742
/content/journals/cchts/10.2174/0113862073255044231027061742
/content/journals/cchts/10.2174/0113862073255044231027061742
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  • Article Type:     Research Article
Keyword(s): breast cancer; estrogen receptor-positive (ER+) breast cancer; fuzheng yiliu formula; molecular docking; Network pharmacology; traditional chinese medicine

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