Skip to content
2000
Volume 20, Issue 1
  • ISSN: 1574-8928
  • E-ISSN: 2212-3970

Abstract

Background

Arginine plays significant and contrasting roles in breast cancer growth and survival. However, the factors governing arginine balance remain poorly characterized.

Objective

We aimed to identify the molecule that governs arginine metabolism in breast cancer and to elucidate its significance.

Methods

We analyzed the correlation between the expression of solute carrier family 7 member 3 (SLC7A3), the major arginine transporter, and breast cancer survival in various databases, including GEPIA, UALCAN, Metascape, String, Oncomine, KM-plotter, CBioPortal and PrognoScan databases. Additionally, we validated our findings through bioinformatic analyses and experimental investigations, including colony formation, wound healing, transwell, and mammosphere formation assays.

Results

Our analysis revealed a significant reduction in SLC7A3 expression in all breast cancer subtypes compared to adjacent breast tissues. Kaplan-Meier survival analyses demonstrated that high SLC7A3 expression was positively associated with decreased nodal metastasis (HR=0.70, 95% CI [0.55, 0.89]), ER positivity (HR=0.79, 95% CI [0.65, 0.95]), and HER2 negativity (HR=0.69, 95% CI [0.58, 0.82]), and increased recurrence-free survival. Moreover, low SLC7A3 expression predicted poor prognosis in breast cancer patients for overall survival. Additionally, the knockdown of SLC7A3 in MCF-7 and MDA-MB-231 cells resulted in increased cell proliferation and invasion .

Conclusion

Our findings indicate a downregulation of SLC7A3 expression in breast cancer tissues compared to adjacent breast tissues. High SLC7A3 expression could serve as a prognostic indicator for favorable outcomes in breast cancer patients due to its inhibitory effects on breast cancer cell proliferation and invasion.

© 2025 The Author(s). Published by Bentham Science Publishers. This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
Loading

Article metrics loading...

/content/journals/pra/10.2174/0115748928279007231130070056
2024-01-08
2025-01-06
Loading full text...

Full text loading...

/deliver/fulltext/pra/20/1/PRA-20-1-05.html?itemId=/content/journals/pra/10.2174/0115748928279007231130070056&mimeType=html&fmt=ahah

References

  1. SungH. FerlayJ. SiegelR.L. 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. LiG. HuJ. HuG. Biomarker studies in early detection and prognosis of breast cancer.Adv. Exp. Med. Biol.20171026273910.1007/978‑981‑10‑6020‑5_2 29282678
    [Google Scholar]
  3. LiJ. ChenZ. SuK. ZengJ. Clinicopathological classification and traditional prognostic indicators of breast cancer.Int. J. Clin. Exp. Pathol.20158785008505 26339424
    [Google Scholar]
  4. SheikhM.S. HuangY. Antibody-drug conjugates for breast cancer treatment.Recent Patents Anticancer Drug Discov.202318210811310.2174/1574892817666220729121205 35909271
    [Google Scholar]
  5. Shiomi-MouriY. KousakaJ. AndoT. Clinical significance of circulating tumor cells (CTCs) with respect to optimal cut-off value and tumor markers in advanced/metastatic breast cancer.Breast Cancer201623112012710.1007/s12282‑014‑0539‑x 24906662
    [Google Scholar]
  6. WangW. XuX. TianB. The diagnostic value of serum tumor markers CEA, CA19-9, CA125, CA15-3, and TPS in metastatic breast cancer.Clin. Chim. Acta2017470515510.1016/j.cca.2017.04.023 28457854
    [Google Scholar]
  7. HussonA. Brasse-LagnelC. FairandA. RenoufS. LavoinneA. Argininosuccinate synthetase from the urea cycle to the citrulline-NO cycle.Eur. J. Biochem.200327091887189910.1046/j.1432‑1033.2003.03559.x 12709047
    [Google Scholar]
  8. LiangX. ZhangL. NatarajanS.K. BeckerD.F. Proline mechanisms of stress survival.Antioxid. Redox Signal.2013199998101110.1089/ars.2012.5074 23581681
    [Google Scholar]
  9. SestiliP. AmbroginiP. BarbieriE. New insights into the trophic and cytoprotective effects of creatine in in vitro and in vivo models of cell maturation.Amino Acids20164881897191110.1007/s00726‑015‑2161‑4 26724921
    [Google Scholar]
  10. BhutiaY.D. BabuE. RamachandranS. GanapathyV. Amino Acid transporters in cancer and their relevance to “glutamine addiction”: Novel targets for the design of a new class of anticancer drugs.Cancer Res.20157591782178810.1158/0008‑5472.CAN‑14‑3745 25855379
    [Google Scholar]
  11. ZhangY. ChungS.F. TamS.Y. LeungY.C. GuanX. Arginine deprivation as a strategy for cancer therapy: An insight into drug design and drug combination.Cancer Lett.2021502587010.1016/j.canlet.2020.12.041 33429005
    [Google Scholar]
  12. PizzagalliM.D. BensimonA. Superti-FurgaG. A guide to plasma membrane solute carrier proteins.FEBS J.202128892784283510.1111/febs.15531 32810346
    [Google Scholar]
  13. KlaassenC.D. AleksunesL.M. Xenobiotic, bile acid, and cholesterol transporters: Function and regulation.Pharmacol. Rev.201062119610.1124/pr.109.002014 20103563
    [Google Scholar]
  14. SutherlandR. MeesonA. LowesS. Solute transporters and malignancy: Establishing the role of uptake transporters in breast cancer and breast cancer metastasis.Cancer Metastasis Rev.202039391993210.1007/s10555‑020‑09879‑6 32388639
    [Google Scholar]
  15. Jundong WuQZ FangYutong Detection kit, detection device and application of postoperative recurrence and metastasis of breast cancer. C.N. Patent 116008548A2023
  16. Baker JoffreB. Method of predicting breast cancer prognosis. N.Z.Patent 624700A2016
  17. YanL. HeJ. LiaoX. A comprehensive analysis of the diagnostic and prognostic value associated with the SLC7A family members in breast cancer.Gland Surg.202211238941110.21037/gs‑21‑909 35284318
    [Google Scholar]
  18. GeigerR. RieckmannJ.C. WolfT. L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity.Cell20161673829842.e1310.1016/j.cell.2016.09.031 27745970
    [Google Scholar]
  19. Poillet-PerezL. XieX. ZhanL. Autophagy maintains tumour growth through circulating arginine.Nature2018563773256957310.1038/s41586‑018‑0697‑7 30429607
    [Google Scholar]
  20. BryantJ.P. HeissJ. Banasavadi-SiddegowdaY.K. Arginine methylation in brain tumors: Tumor biology and therapeutic strategies.Cells202110112410.3390/cells10010124 33440687
    [Google Scholar]
  21. SzefelJ. DanielakA. KruszewskiW.J. Metabolic pathways of L-arginine and therapeutic consequences in tumors.Adv. Med. Sci.201964110411010.1016/j.advms.2018.08.018 30605863
    [Google Scholar]
  22. WangS.C.M. DowhanD.H. MuscatG.E.O. Epigenetic arginine methylation in breast cancer: Emerging therapeutic strategies.J. Mol. Endocrinol.2019623R223R23710.1530/JME‑18‑0224 30620710
    [Google Scholar]
  23. RebsamenM. GirardiE. SedlyarovV. Gain-of-function genetic screens in human cells identify SLC transporters overcoming environmental nutrient restrictions.Life Sci. Alliance2022511e20220140410.26508/lsa.202201404 36114003
    [Google Scholar]
  24. ChandrashekarD.S. KarthikeyanS.K. KorlaP.K. UALCAN: An update to the integrated cancer data analysis platform.Neoplasia202225182710.1016/j.neo.2022.01.001 35078134
    [Google Scholar]
  25. TangZ. LiC. KangB. GaoG. LiC. ZhangZ. GEPIA: A web server for cancer and normal gene expression profiling and interactive analyses.Nucleic Acids Res.201745W1W98W10210.1093/nar/gkx247 28407145
    [Google Scholar]
  26. ChenX. WangL. SuX. LuoS. TangX. HuangY. Identification of potential target genes and crucial pathways in small cell lung cancer based on bioinformatic strategy and human samples.PLoS One20201511e024219410.1371/journal.pone.0242194 33186389
    [Google Scholar]
  27. WuP. HeinsZ.J. MullerJ.T. Integration and analysis of CPTAC proteomics data in the context of cancer genomics in the cBioPortal.Mol. Cell. Proteomics20191891893189810.1074/mcp.TIR119.001673 31308250
    [Google Scholar]
  28. ZhouY. ZhouB. PacheL. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets.Nat. Commun.2019101152310.1038/s41467‑019‑09234‑6 30944313
    [Google Scholar]
  29. YoshiharaK. ShahmoradgoliM. MartínezE. Inferring tumour purity and stromal and immune cell admixture from expression data.Nat. Commun.201341261210.1038/ncomms3612 24113773
    [Google Scholar]
  30. HeL.F. XuH.W. ChenM. Activated-PAK4 predicts worse prognosis in breast cancer and promotes tumorigenesis through activation of PI3K/AKT signaling.Oncotarget2017811175731758510.18632/oncotarget.7466 28407679
    [Google Scholar]
  31. KolakA. KamińskaM. SygitK. Primary and secondary prevention of breast cancer.Ann. Agric. Environ. Med.201724454955310.26444/aaem/75943 29284222
    [Google Scholar]
  32. RenW. ChenM. QiaoY. ZhaoF. Global guidelines for breast cancer screening: A systematic review.Breast202264859910.1016/j.breast.2022.04.003 35636342
    [Google Scholar]
  33. JamshidiA. LiuM.C. KleinE.A. Evaluation of cell-free DNA approaches for multi-cancer early detection.Cancer Cell2022401215371549.e1210.1016/j.ccell.2022.10.022 36400018
    [Google Scholar]
  34. da Costa VieiraR.A. BillerG. UemuraG. RuizC.A. CuradoM.P. Breast cancer screening in developing countries.Clinics201772424425310.6061/clinics/2017(04)09 28492725
    [Google Scholar]
  35. JonesS. HrubanR.H. KamiyamaM. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene.Science2009324592421710.1126/science.1171202 19264984
    [Google Scholar]
  36. CallahanK.E. PinheiroP.S. CvijeticN. KellyR.E. PonceC.P. KobetzE.N. Worse breast cancer outcomes for southern nevadans, filipina and black women.J. Immigr. Minor. Health20171961330133710.1007/s10903‑016‑0475‑2 27480158
    [Google Scholar]
  37. ShenL. QianC. CaoH. WangZ. LuoT. LiangC. Upregulation of the solute carrier family 7 genes is indicative of poor prognosis in papillary thyroid carcinoma.World J. Surg. Oncol.201816123510.1186/s12957‑018‑1535‑y 30558624
    [Google Scholar]
  38. LowmanX.H. HanseE.A. YangY. p53 promotes cancer cell adaptation to glutamine deprivation by upregulating Slc7a3 to increase arginine uptake.Cell Rep.2019261130513060.e410.1016/j.celrep.2019.02.037 30865893
    [Google Scholar]
  39. De LucaA. LamuraL. GalloM. MaffiaV. NormannoN. Mesenchymal stem cell‐derived interleukin‐6 and vascular endothelial growth factor promote breast cancer cell migration.J. Cell. Biochem.2012113113363337010.1002/jcb.24212 22644871
    [Google Scholar]
  40. KarnoubA.E. DashA.B. VoA.P. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis.Nature2007449716255756310.1038/nature06188 17914389
    [Google Scholar]
  41. FalleniM. SaviF. TosiD. M1 and M2 macrophages’ clinicopathological significance in cutaneous melanoma.Melanoma Res.201727320021010.1097/CMR.0000000000000352 28272106
    [Google Scholar]
  42. WangP. SongY. LiH. SIRPA enhances osteosarcoma metastasis by stabilizing SP1 and promoting SLC7A3-mediated arginine uptake.Cancer Lett.202357621641210.1016/j.canlet.2023.216412 37769797
    [Google Scholar]
/content/journals/pra/10.2174/0115748928279007231130070056
Loading
/content/journals/pra/10.2174/0115748928279007231130070056
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher’s website along with the published article.


  • Article Type:
    Research Article
Keyword(s): arginine; breast cancer; cell proliferation; prognosis; SLC7A3; tumor suppressor
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test