Skip to content
2000
image of Analysis of Endoplasmic Reticulum Stress-Associated Proteins As Prognostic Markers In Breast Cancer

Abstract

Introduction

Breast cancer is a complex, heterogeneous disease that poses a significant global health risk. Both internal and external cellular stresses contribute to breast cancer progression. Endoplasmic reticulum (ER) stress is one such cellular stress response that activates intricate intracellular signaling pathways collectively known as the unfolded protein response (UPR). Maintaining protein homeostasis and regulating these pathways is essential in breast cancer progression.

Methods

Using STRING and Harmonizome Reactome pathway datasets, we identified a list of UPR-associated genes. The Human Protein Atlas and UALCAN databases were used to analyze these genes as potential prognostic markers in breast cancer.

Results

Three prognostic markers were identified in patients with breast cancer: FK506 binding protein 14 (FKBP14), S-phase kinase-associated protein 1 (SKP1), and Baculoviral IAP repeat containing 3 (BIRC3).

Discussion

Expression levels of FKBP14, SKP1, and BIRC3 were compared to TCGA normal and GTEx data using the GEPIA2 database. Our analysis indicates that higher SKP1 expression is associated with poor overall survival and prognosis, whereas higher BIRC3 expression correlates with better prognosis and overall survival. BIRC3 protein levels are elevated in tumor tissue and increase as the tumor progresses through various stages. Additionally, the expression of these markers varies according to sex, age, ethnicity, breast cancer subtype, nodal metastasis, and menopause status.

Conclusion

Overall, our study identifies that the genes involved in ER stress that are associated with breast cancer can serve as prognostic markers.

Loading

Article metrics loading...

/content/journals/cg/10.2174/0113892029374158251030064845
2026-01-06
2026-02-25
Loading full text...

Full text loading...

References

  1. Bray F. Laversanne M. Sung H. Ferlay J. Siegel R.L. Soerjomataram I. Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2024 74 3 229 263 10.3322/caac.21834 38572751
    [Google Scholar]
  2. Zhang B. Beeghly-Fadiel A. Long J. Zheng W. Genetic variants associated with breast-cancer risk: Comprehensive research synopsis, meta-analysis, and epidemiological evidence. Lancet Oncol. 2011 12 5 477 488 10.1016/S1470‑2045(11)70076‑6 21514219
    [Google Scholar]
  3. Herrera-Quintana L. Vázquez-Lorente H. Plaza-Diaz J. Breast cancer: Extracellular matrix and microbiome interactions. Int. J. Mol. Sci. 2024 25 13 7226 10.3390/ijms25137226 39000333
    [Google Scholar]
  4. Hibino S. Kawazoe T. Kasahara H. Itoh S. Ishimoto T. Sakata-Yanagimoto M. Taniguchi K. Inflammation-induced tumorigenesis and metastasis. Int. J. Mol. Sci. 2021 22 11 5421 10.3390/ijms22115421 34063828
    [Google Scholar]
  5. Anderson N.M. Simon M.C. The tumor microenvironment. Curr. Biol. 2020 30 16 R921 R925 10.1016/j.cub.2020.06.081 32810447
    [Google Scholar]
  6. Pinheiro M. Drigo S.A. Tonhosolo R. Andrade S.C.S. Marchi F.A. Jurisica I. Kowalski L.P. Achatz M.I. Rogatto S.R. HABP2 p.G534E variant in patients with family history of thyroid and breast cancer. Oncotarget 2017 8 25 40896 40905 10.18632/oncotarget.16639 28402931
    [Google Scholar]
  7. Jain B.P. An overview of unfolded protein response signaling and its role in cancer. Cancer Biother. Radiopharm. 2017 32 8 275 281 10.1089/cbr.2017.2309 29053418
    [Google Scholar]
  8. Yadav R.K. Chae S.W. Kim H.R. Chae H.J. Endoplasmic reticulum stress and cancer. J. Cancer Prev 2014 19 2 75 88 10.15430/JCP.2014.19.2.75 25337575
    [Google Scholar]
  9. Martinon F. Targeting endoplasmic reticulum signaling pathways in cancer. Acta Oncol. 2012 51 7 822 830 10.3109/0284186X.2012.689113 22686473
    [Google Scholar]
  10. Walter P. Ron D. The unfolded protein response: From stress pathway to homeostatic regulation. Science 2011 334 6059 1081 1086 10.1126/science.1209038 22116877
    [Google Scholar]
  11. Merksamer P.I. Papa F.R. The UPR and cell fate at a glance. J. Cell. Sci. 2010 123 7 1003 1006 10.1242/jcs.035832 20332117
    [Google Scholar]
  12. Fernandez P.M. Tabbara S.O. Jacobs L.K. Manning F.C.R. Tsangaris T.N. Schwartz A.M. Kennedy K.A. Patierno S.R. Overexpression of the glucose-regulated stress gene GRP78 in malignant but not benign human breast lesions. Breast Cancer Res. Treat. 2000 59 1 15 26 10.1023/A:1006332011207 10752676
    [Google Scholar]
  13. Uramoto H. Sugio K. Oyama T. Nakata S. Ono K. Yoshimastu T. Morita M. Yasumoto K. Expression of endoplasmic reticulum molecular chaperone Grp78 in human lung cancer and its clinical significance. Lung Cancer 2005 49 1 55 62 10.1016/j.lungcan.2004.12.011 15949590
    [Google Scholar]
  14. Choi S. Encyclopedia of Signaling Molecules. Cham Springer International Publishing 2018 10.1007/978‑3‑319‑67199‑4
    [Google Scholar]
  15. Fischer G. Aumüller T. Regulation of peptide bond cis/trans isomerization by enzyme catalysis and its implication in physiological processes. Rev. Physiol. Biochem. Pharmacol. 2003 148 105 150 10.1007/s10254‑003‑0011‑3 12698322
    [Google Scholar]
  16. Tong M. Jiang Y. FK506-binding proteins and their diverse functions. Curr. Mol. Pharmacol. 2015 9 1 48 65 10.2174/1874467208666150519113541 25986568
    [Google Scholar]
  17. Ghartey-Kwansah G. Li Z. Feng R. Wang L. Zhou X. Chen F.Z. Xu M.M. Jones O. Mu Y. Chen S. Bryant J. Isaacs W.B. Ma J. Xu X. Comparative analysis of FKBP family protein: Evaluation, structure, and function in mammals and Drosophila melanogaster. BMC Dev. Biol. 2018 18 1 7 10.1186/s12861‑018‑0167‑3 29587629
    [Google Scholar]
  18. Jia X Huang R Xian S Unraveling the unfolded protein response signature: Implications for tumor immune microenvironment heterogeneity and clinical prognosis in stomach cancer. Aging 2024 16 7818 7844 10.18632/aging.205784
    [Google Scholar]
  19. Bursztejn A.C. Baumann M. Lipsker D. Ehlers-Danlos syndrome related to FKBP14 mutations: Detailed cutaneous phenotype. Clin. Exp. Dermatol. 2017 42 1 64 67 10.1111/ced.12983 27905128
    [Google Scholar]
  20. Ghoorun R.A. Wu X.H. Chen H.L. Ren D.L. Wu X.B. Prognostic significance of FKBP14 in gastric cancer. OncoTargets Ther. 2019 12 11567 11577 10.2147/OTT.S221943 31920344
    [Google Scholar]
  21. Khanna P. Lee J.S. Sereemaspun A. Lee H. Baeg G.H. GRAMD1B regulates cell migration in breast cancer cells through JAK/STAT and Akt signaling. Sci. Rep 2018 8 1 9511 10.1038/s41598‑018‑27864‑6 29934528
    [Google Scholar]
  22. Ishikawa Y. Bächinger H.P. A substrate preference for the rough endoplasmic reticulum resident protein FKBP22 during collagen biosynthesis. J. Biol. Chem. 2014 289 26 18189 18201 10.1074/jbc.M114.561944 24821723
    [Google Scholar]
  23. Zhang Q. An Z.Y. Jiang W. Jin W.L. He X.Y. Collagen code in tumor microenvironment: Functions, molecular mechanisms, and therapeutic implications. Biomed. Pharmacother 2023 166 115390 10.1016/j.biopha.2023.115390 37660648
    [Google Scholar]
  24. van de Hoef D.L. Bonner J.M. Boulianne G.L. FKBP14 is an essential gene that regulates Presenilin protein levels and Notch signaling in Drosophila. Development 2013 140 4 810 819 10.1242/dev.081356 23318643
    [Google Scholar]
  25. Azimi M. Le T.T. Brown N.L. Presenilin gene function and Notch signaling feedback regulation in the developing mouse lens. Differentiation 2018 102 40 52 10.1016/j.diff.2018.07.003 30059908
    [Google Scholar]
  26. Shi Q. Xue C. Zeng Y. Yuan X. Chu Q. Jiang S. Wang J. Zhang Y. Zhu D. Li L. Notch signaling pathway in cancer: From mechanistic insights to targeted therapies. Signal. Transduct Target. Ther 2024 9 1 128 10.1038/s41392‑024‑01828‑x 38797752
    [Google Scholar]
  27. Carrano A.C. Eytan E. Hershko A. Pagano M. SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nat. Cell Biol. 1999 1 4 193 199 10.1038/12013 10559916
    [Google Scholar]
  28. Han C. Jin L. Mei Y. Wu M. Endoplasmic reticulum stress inhibits cell cycle progression via induction of p27 in melanoma cells. Cell. Signal. 2013 25 1 144 149 10.1016/j.cellsig.2012.09.023 23010535
    [Google Scholar]
  29. Zhang K. Liu H. Song Z. Jiang Y. Kim H. Samavati L. Nguyen H.M. Yang Z.Q. The UPR transducer IRE1 promotes breast cancer malignancy by degrading tumor suppressor microRNAs. iScience 2020 23 9 101503 10.1016/j.isci.2020.101503 32911332
    [Google Scholar]
  30. Zhang L. Chen H. Brandizzi F. Verchot J. Wang A. The UPR branch IRE1-bZIP60 in plants plays an essential role in viral infection and is complementary to the only UPR pathway in yeast. PLoS Genet. 2015 11 4 1005164 10.1371/journal.pgen.1005164 25875739
    [Google Scholar]
  31. Tsvetkov L.M. Yeh K.H. Lee S.J. Sun H. Zhang H. p27Kip1 ubiquitination and degradation is regulated by the SCFSkp2 complex through phosphorylated Thr187 in p27. Curr. Biol. 1999 9 12 661 S2 10.1016/S0960‑9822(99)80290‑5 10375532
    [Google Scholar]
  32. Makuch-Kocka A. Kocki J. Brzozowska A. Bogucki J. Kołodziej P. Płachno B.J. Bogucka-Kocka A. The BIRC family genes expression in patients with triple negative breast cancer. Int. J. Mol. Sci. 2021 22 4 1820 10.3390/ijms22041820 33673050
    [Google Scholar]
  33. Scull C.M. Tabas I. Mechanisms of ER stress-induced apoptosis in atherosclerosis. Arterioscler Thromb Vasc Biol. 2011 31 12 2792 2797 10.1161/ATVBAHA.111.224881 22096099
    [Google Scholar]
  34. Urano F. Wang X. Bertolotti A. Zhang Y. Chung P. Harding H.P. Ron D. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 2000 287 5453 664 666 10.1126/science.287.5453.664 10650002
    [Google Scholar]
  35. Rouillard A.D. Gundersen G.W. Fernandez N.F. Wang Z. Monteiro C.D. McDermott M.G. Ma’ayan A. The harmonizome: A collection of processed datasets gathered to serve and mine knowledge about genes and proteins. Database 2016 2016 baw100 10.1093/database/baw100 27374120
    [Google Scholar]
  36. Szklarczyk D. Gable A.L. Lyon D. Junge A. Wyder S. Huerta-Cepas J. Simonovic M. Doncheva N.T. Morris J.H. Bork P. Jensen L.J. Mering C. STRING v11: Protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019 47 D1 D607 D613 10.1093/nar/gky1131 30476243
    [Google Scholar]
  37. The cancer genome atlas program (TCGA). 2022 Available from:https://www.cancer.gov/ccg/research/genome-sequencing/tcga
  38. Uhlen M. Zhang C. Lee S. Sjöstedt E. Fagerberg L. Bidkhori G. Benfeitas R. Arif M. Liu Z. Edfors F. Sanli K. von Feilitzen K. Oksvold P. Lundberg E. Hober S. Nilsson P. Mattsson J. Schwenk J.M. Brunnström H. Glimelius B. Sjöblom T. Edqvist P.H. Djureinovic D. Micke P. Lindskog C. Mardinoglu A. Ponten F. A pathology atlas of the human cancer transcriptome. Science 2017 357 6352 eaan2507 10.1126/science.aan2507 28818916
    [Google Scholar]
  39. GEPIA 2. 2020 Available from:http://gepia2.cancer-pku.cn/#index
  40. UALCAN. 2021 Available from:https://ualcan.path.uab.edu/
  41. Jayaraman T. Lee Y.Y. Chan W.K. Mahadeva S. Epidemiological differences of common liver conditions between Asia and the West. JGH Open 2020 4 3 332 339 10.1002/jgh3.12275 32514433
    [Google Scholar]
  42. Pal S.K. Hurria A. Impact of age, sex, and comorbidity on cancer therapy and disease progression. J. Clin. Oncol. 2010 28 26 4086 4093 10.1200/JCO.2009.27.0579 20644100
    [Google Scholar]
  43. Fares J. Fares M.Y. Khachfe H.H. Salhab H.A. Fares Y. Molecular principles of metastasis: A hallmark of cancer revisited. Signal Transduct. Target. Ther. 2020 5 1 28 10.1038/s41392‑020‑0134‑x 32296047
    [Google Scholar]
  44. Łukasiewicz S. Czeczelewski M. Forma A. Baj J. Sitarz R. Stanisławek A. Breast cancer—epidemiology, risk factors, classification, prognostic markers, and current treatment strategies—an updated review. Cancers 2021 13 17 4287 10.3390/cancers13174287 34503097
    [Google Scholar]
  45. Mahmood A. Srivastava R. Chapter 3 - etiology of cancer. In: Understanding Cancer; Jain B Pandey S United States Academic Press 2022 37 62 10.1016/B978‑0‑323‑99883‑3.00008‑1
    [Google Scholar]
  46. Frazzi R. BIRC3 and BIRC5: Multi‐faceted inhibitors in cancer. Cell Biosci. 2021 11 1 8 10.1186/s13578‑020‑00521‑0 33413657
    [Google Scholar]
  47. Quijada-Álamo M. Hernández-Sánchez M. Rodríguez-Vicente A.E. Pérez-Carretero C. Rodríguez-Sánchez A. Martín-Izquierdo M. Alonso-Pérez V. García-Tuñón I. Bastida J.M. Vidal-Manceñido M.J. Galende J. Aguilar C. Queizán J.A. González-Gascón y Marín I. Hernández-Rivas J.Á. Benito R. Ordóñez J.L. Hernández-Rivas J.M. Biological significance of monoallelic and biallelic BIRC3 loss in del(11q) chronic lymphocytic leukemia progression. Blood Cancer J. 2021 11 7 127 10.1038/s41408‑021‑00520‑5 34244476
    [Google Scholar]
  48. Read A. Schröder M. The unfolded protein response: An overview. Biology 2021 10 5 384 10.3390/biology10050384 33946669
    [Google Scholar]
  49. Cao S.S. Kaufman R.J. Unfolded protein response. Curr. Biol. 2012 22 16 R622 R626 10.1016/j.cub.2012.07.004 22917505
    [Google Scholar]
  50. Chakrabarti A. Chen A.W. Varner J.D. A review of the mammalian unfolded protein response. Biotechnol. Bioeng. 2011 108 12 2777 2793 10.1002/bit.23282 21809331
    [Google Scholar]
  51. Vandewynckel Y-P. Laukens D. Geerts A. Bogaerts E. Paridaens A. Verhelst X. Janssens S. Heindryckx F. Van Vlierberghe H. The paradox of the unfolded protein response in cancer. Anticancer Res. 2013 33 11 4683 4694 24222102
    [Google Scholar]
/content/journals/cg/10.2174/0113892029374158251030064845
Loading
/content/journals/cg/10.2174/0113892029374158251030064845
Loading

Data & Media loading...

Supplements

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

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