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Erschienen in: Advances in Therapy 9/2023

09.07.2023 | Original Research

Study on the Relationship Between Differentially Expressed Proteins in Breast Cancer and Lymph Node Metastasis

verfasst von: Yu-Lu Sun, Yi-Xin Zhao, Yi-Nan Guan, Xin You, Yin Zhang, Meng Zhang, Hong-Yan Wu, Wei-Jie Zhang, Yong-Zhong Yao

Erschienen in: Advances in Therapy | Ausgabe 9/2023

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Abstract

Introduction

Lymph node metastasis is a cause of poor prognosis in breast cancer. Mass spectrometry-based proteomics aims to map the protein landscapes of biological samples and profile tumors more comprehensively. Here, proteomics was employed to identify differentially expressed proteins (DEPs) that were associated with lymph node metastasis.

Methods

Tandem mass tag (TMT) quantitative proteomic approaches were applied for extensive profiling of conditioned medium of MDA-MB-231 and MCF7 cell lines and serums of patients who did or did not have lymph node metastasis, and DEPs were analyzed by bioinformatics. Furthermore, potential secreted or membrane proteins MUC5AC, ITGB4, CTGF, EphA2, S100A4, PRDX2, and PRDX6 were selected for verification in 114 tissue microarray samples of breast cancer using the immunohistochemical method. The relevant data was analyzed and processed by independent sample t test, chi-square test, or Fisher’s exact test using SPSS 22.0 software.

Results

In the conditioned medium of MDA-MB-231 cell lines, 154 proteins were upregulated, while 136 were downregulated compared to those of MCF7. In the serum of patients with breast cancer and lymph node metastasis, 17 proteins were upregulated, and 5 proteins were downregulated compared to those without lymph node metastasis. Furthermore, according to tissue verification, CTGF, EphA2, S100A4, and PRDX2 were associated with breast cancer lymph node metastasis.

Conclusion

Our study provides a new perspective for the understanding of the role of DEPs (especially CTGF, EphA2, S100A4, and PRDX2) in the development and metastasis of breast cancer. They could become potential diagnostic and prognostic biomarkers and therapeutic targets.
Literatur
1.
Zurück zum Zitat Siegel RL, Miller KD, Wagle NS, et al. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17–48.PubMedCrossRef Siegel RL, Miller KD, Wagle NS, et al. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17–48.PubMedCrossRef
2.
Zurück zum Zitat Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49.CrossRefPubMed Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49.CrossRefPubMed
4.
Zurück zum Zitat Ureyen O, Cavdar DK, Adibelli ZH, et al. Axillary metastasis in clinically node-negative breast cancer. J Egypt Natl Canc Inst. 2018;30(4):159–63.PubMedCrossRef Ureyen O, Cavdar DK, Adibelli ZH, et al. Axillary metastasis in clinically node-negative breast cancer. J Egypt Natl Canc Inst. 2018;30(4):159–63.PubMedCrossRef
5.
Zurück zum Zitat Xiao M, Yang S, Meng F, et al. LAPTM4B predicts axillary lymph node metastasis in breast cancer and promotes breast cancer cell aggressiveness in vitro. Cell Physiol Biochem. 2017;41(3):1072–82.PubMedCrossRef Xiao M, Yang S, Meng F, et al. LAPTM4B predicts axillary lymph node metastasis in breast cancer and promotes breast cancer cell aggressiveness in vitro. Cell Physiol Biochem. 2017;41(3):1072–82.PubMedCrossRef
6.
7.
Zurück zum Zitat Morrow M. Personalizing extent of breast cancer surgery according to molecular subtypes. Breast. 2013;22(Suppl 2):S106–9.PubMedCrossRef Morrow M. Personalizing extent of breast cancer surgery according to molecular subtypes. Breast. 2013;22(Suppl 2):S106–9.PubMedCrossRef
8.
Zurück zum Zitat Shiino S, Matsuzaki J, Shimomura A, et al. Serum miRNA-based prediction of axillary lymph node metastasis in breast cancer. Clin Cancer Res. 2019;25(6):1817–27.PubMedCrossRef Shiino S, Matsuzaki J, Shimomura A, et al. Serum miRNA-based prediction of axillary lymph node metastasis in breast cancer. Clin Cancer Res. 2019;25(6):1817–27.PubMedCrossRef
9.
Zurück zum Zitat Bose U, Wijffels G, Howitt CA, et al. Proteomics: tools of the trade. Adv Exp Med Biol. 2019;1073:1–22.PubMedCrossRef Bose U, Wijffels G, Howitt CA, et al. Proteomics: tools of the trade. Adv Exp Med Biol. 2019;1073:1–22.PubMedCrossRef
10.
Zurück zum Zitat Monti C, Zilocchi M, Colugnat I, et al. Proteomics turns functional. J Proteomics. 2019;198:36–44.PubMedCrossRef Monti C, Zilocchi M, Colugnat I, et al. Proteomics turns functional. J Proteomics. 2019;198:36–44.PubMedCrossRef
11.
Zurück zum Zitat Gajbhiye A, Dabhi R, Taunk K, et al. Multipronged quantitative proteomics reveals serum proteome alterations in breast cancer intrinsic subtypes. J Proteomics. 2017;163:1–13.PubMedCrossRef Gajbhiye A, Dabhi R, Taunk K, et al. Multipronged quantitative proteomics reveals serum proteome alterations in breast cancer intrinsic subtypes. J Proteomics. 2017;163:1–13.PubMedCrossRef
12.
Zurück zum Zitat Yigitbasi T, Calibasi-Kocal G, Buyukuslu N, et al. An efficient biomarker panel for diagnosis of breast cancer using surface-enhanced laser desorption ionization time-of-flight mass spectrometry. Biomed Rep. 2018;8(3):269–74.PubMedPubMedCentral Yigitbasi T, Calibasi-Kocal G, Buyukuslu N, et al. An efficient biomarker panel for diagnosis of breast cancer using surface-enhanced laser desorption ionization time-of-flight mass spectrometry. Biomed Rep. 2018;8(3):269–74.PubMedPubMedCentral
13.
Zurück zum Zitat Mueller C, Haymond A, Davis JB, et al. Protein biomarkers for subtyping breast cancer and implications for future research. Expert Rev Proteomics. 2018;15(2):131–52.PubMedPubMedCentralCrossRef Mueller C, Haymond A, Davis JB, et al. Protein biomarkers for subtyping breast cancer and implications for future research. Expert Rev Proteomics. 2018;15(2):131–52.PubMedPubMedCentralCrossRef
14.
Zurück zum Zitat Zhang J, Tang N, Zhao Y, et al. Global phosphoproteomic analysis reveals significant metabolic reprogramming in the termination of liver regeneration in mice. J Proteome Res. 2020;19(4):1788–99.PubMedPubMedCentralCrossRef Zhang J, Tang N, Zhao Y, et al. Global phosphoproteomic analysis reveals significant metabolic reprogramming in the termination of liver regeneration in mice. J Proteome Res. 2020;19(4):1788–99.PubMedPubMedCentralCrossRef
15.
Zurück zum Zitat Gao X, Zhang L, Zhou P, et al. Tandem mass tag-based quantitative proteome analysis of porcine deltacoronavirus (PDCoV)-infected LLC porcine kidney cells. ACS Omega. 2020;5(35):21979–87.PubMedPubMedCentralCrossRef Gao X, Zhang L, Zhou P, et al. Tandem mass tag-based quantitative proteome analysis of porcine deltacoronavirus (PDCoV)-infected LLC porcine kidney cells. ACS Omega. 2020;5(35):21979–87.PubMedPubMedCentralCrossRef
16.
Zurück zum Zitat Chen ST, Pan TL, Juan HF, et al. Breast tumor microenvironment: proteomics highlights the treatments targeting secretome. J Proteome Res. 2008;7(4):1379–87.PubMedPubMedCentralCrossRef Chen ST, Pan TL, Juan HF, et al. Breast tumor microenvironment: proteomics highlights the treatments targeting secretome. J Proteome Res. 2008;7(4):1379–87.PubMedPubMedCentralCrossRef
17.
Zurück zum Zitat Kulasingam V, Diamandis EP. Proteomics analysis of conditioned media from three breast cancer cell lines: a mine for biomarkers and therapeutic targets. Mol Cell Proteomics. 2007;6(11):1997–2011.PubMedCrossRef Kulasingam V, Diamandis EP. Proteomics analysis of conditioned media from three breast cancer cell lines: a mine for biomarkers and therapeutic targets. Mol Cell Proteomics. 2007;6(11):1997–2011.PubMedCrossRef
18.
Zurück zum Zitat Liotta LA, Ferrari M, Petricoin E. Clinical proteomics: written in blood. Nature. 2003;425(6961):905.PubMedCrossRef Liotta LA, Ferrari M, Petricoin E. Clinical proteomics: written in blood. Nature. 2003;425(6961):905.PubMedCrossRef
19.
Zurück zum Zitat Mange A, Dimitrakopoulos L, Soosaipillai A, et al. An integrated cell line-based discovery strategy identified follistatin and kallikrein 6 as serum biomarker candidates of breast carcinoma. J Proteomics. 2016;142:114–21.PubMedCrossRef Mange A, Dimitrakopoulos L, Soosaipillai A, et al. An integrated cell line-based discovery strategy identified follistatin and kallikrein 6 as serum biomarker candidates of breast carcinoma. J Proteomics. 2016;142:114–21.PubMedCrossRef
20.
Zurück zum Zitat Kim H, Son S, Ko Y, et al. CTGF regulates cell proliferation, migration, and glucose metabolism through activation of FAK signaling in triple-negative breast cancer. Oncogene. 2021;40(15):2667–81.PubMedCrossRef Kim H, Son S, Ko Y, et al. CTGF regulates cell proliferation, migration, and glucose metabolism through activation of FAK signaling in triple-negative breast cancer. Oncogene. 2021;40(15):2667–81.PubMedCrossRef
21.
Zurück zum Zitat Takigawa M. An early history of CCN2/CTGF research: the road to CCN2 via hcs24, ctgf, ecogenin, and regenerin. J Cell Commun Signal. 2018;12(1):253–64.PubMedCrossRef Takigawa M. An early history of CCN2/CTGF research: the road to CCN2 via hcs24, ctgf, ecogenin, and regenerin. J Cell Commun Signal. 2018;12(1):253–64.PubMedCrossRef
22.
Zurück zum Zitat Kim B, Kim H, Jung S, et al. A CTGF-RUNX2-RANKL axis in breast and prostate cancer cells promotes tumor progression in bone. J Bone Miner Res. 2020;35(1):155–66.PubMedCrossRef Kim B, Kim H, Jung S, et al. A CTGF-RUNX2-RANKL axis in breast and prostate cancer cells promotes tumor progression in bone. J Bone Miner Res. 2020;35(1):155–66.PubMedCrossRef
23.
Zurück zum Zitat Wells JE, Howlett M, Cole CH, et al. Deregulated expression of connective tissue growth factor (CTGF/CCN2) is linked to poor outcome in human cancer. Int J Cancer. 2015;137(3):504–11.PubMedCrossRef Wells JE, Howlett M, Cole CH, et al. Deregulated expression of connective tissue growth factor (CTGF/CCN2) is linked to poor outcome in human cancer. Int J Cancer. 2015;137(3):504–11.PubMedCrossRef
24.
Zurück zum Zitat Niu J, Ma J, Guan X, et al. Correlation between Doppler ultrasound blood flow parameters and angiogenesis and proliferation activity in breast cancer. Med Sci Monit. 2019;25:7035–41.PubMedPubMedCentralCrossRef Niu J, Ma J, Guan X, et al. Correlation between Doppler ultrasound blood flow parameters and angiogenesis and proliferation activity in breast cancer. Med Sci Monit. 2019;25:7035–41.PubMedPubMedCentralCrossRef
25.
Zurück zum Zitat Hellinger JW, Schomel F, Buse JV, et al. Identification of drivers of breast cancer invasion by secretome analysis: insight into CTGF signaling. Sci Rep. 2020;10(1):17889.PubMedPubMedCentralCrossRef Hellinger JW, Schomel F, Buse JV, et al. Identification of drivers of breast cancer invasion by secretome analysis: insight into CTGF signaling. Sci Rep. 2020;10(1):17889.PubMedPubMedCentralCrossRef
26.
Zurück zum Zitat Okuyama T, Sakamoto R, Kumagai K, et al. EPHA2 antisense RNA modulates EPHA2 mRNA levels in basal-like/triple-negative breast cancer cells. Biochimie. 2020;179:169–80.PubMedCrossRef Okuyama T, Sakamoto R, Kumagai K, et al. EPHA2 antisense RNA modulates EPHA2 mRNA levels in basal-like/triple-negative breast cancer cells. Biochimie. 2020;179:169–80.PubMedCrossRef
27.
Zurück zum Zitat Zhang T, Li J, Ma X, et al. Inhibition of HDACs-EphA2 signaling axis with WW437 demonstrates promising preclinical antitumor activity in breast cancer. EBioMedicine. 2018;31:276–86.PubMedPubMedCentralCrossRef Zhang T, Li J, Ma X, et al. Inhibition of HDACs-EphA2 signaling axis with WW437 demonstrates promising preclinical antitumor activity in breast cancer. EBioMedicine. 2018;31:276–86.PubMedPubMedCentralCrossRef
28.
Zurück zum Zitat Mitra D, Bhattacharyya S, Alam N, et al. Phosphorylation of EphA2 receptor and vasculogenic mimicry is an indicator of poor prognosis in invasive carcinoma of the breast. Breast Cancer Res Treat. 2020;179(2):359–70.PubMedCrossRef Mitra D, Bhattacharyya S, Alam N, et al. Phosphorylation of EphA2 receptor and vasculogenic mimicry is an indicator of poor prognosis in invasive carcinoma of the breast. Breast Cancer Res Treat. 2020;179(2):359–70.PubMedCrossRef
29.
Zurück zum Zitat Anderton M, van der Meulen E, Blumenthal MJ, et al. The role of the Eph receptor family in tumorigenesis. Cancers (Basel). 2021;13(2):206.PubMedCrossRef Anderton M, van der Meulen E, Blumenthal MJ, et al. The role of the Eph receptor family in tumorigenesis. Cancers (Basel). 2021;13(2):206.PubMedCrossRef
30.
Zurück zum Zitat Zhou Y, Sakurai H. Emerging and diverse functions of the EphA2 noncanonical pathway in cancer progression. Biol Pharm Bull. 2017;40(10):1616–24.PubMedCrossRef Zhou Y, Sakurai H. Emerging and diverse functions of the EphA2 noncanonical pathway in cancer progression. Biol Pharm Bull. 2017;40(10):1616–24.PubMedCrossRef
31.
32.
Zurück zum Zitat Gonzalez LL, Garrie K, Turner MD. Role of S100 proteins in health and disease. Biochim Biophys Acta Mol Cell Res. 2020;1867(6): 118677.PubMedCrossRef Gonzalez LL, Garrie K, Turner MD. Role of S100 proteins in health and disease. Biochim Biophys Acta Mol Cell Res. 2020;1867(6): 118677.PubMedCrossRef
33.
Zurück zum Zitat Wen X, Yu X, Tian Y, et al. Quantitative shear wave elastography in primary invasive breast cancers, based on collagen-S100A4 pathology, indicates axillary lymph node metastasis. Quant Imaging Med Surg. 2020;10(3):624–33.PubMedPubMedCentralCrossRef Wen X, Yu X, Tian Y, et al. Quantitative shear wave elastography in primary invasive breast cancers, based on collagen-S100A4 pathology, indicates axillary lymph node metastasis. Quant Imaging Med Surg. 2020;10(3):624–33.PubMedPubMedCentralCrossRef
35.
Zurück zum Zitat Liu Y, Geng YH, Yang H, et al. Extracellular ATP drives breast cancer cell migration and metastasis via S100A4 production by cancer cells and fibroblasts. Cancer Lett. 2018;430:1–10.PubMedCrossRef Liu Y, Geng YH, Yang H, et al. Extracellular ATP drives breast cancer cell migration and metastasis via S100A4 production by cancer cells and fibroblasts. Cancer Lett. 2018;430:1–10.PubMedCrossRef
36.
Zurück zum Zitat Ismail TM, Fernig DG, Rudland PS, et al. The basic C-terminal amino acids of calcium-binding protein S100A4 promote metastasis. Carcinogenesis. 2008;29(12):2259–66.PubMedCrossRef Ismail TM, Fernig DG, Rudland PS, et al. The basic C-terminal amino acids of calcium-binding protein S100A4 promote metastasis. Carcinogenesis. 2008;29(12):2259–66.PubMedCrossRef
38.
Zurück zum Zitat Chen Y, Yang S, Zhou H, et al. PRDX2 promotes the proliferation and metastasis of non-small cell lung cancer in vitro and in vivo. Biomed Res Int. 2020;2020:8359860.PubMedPubMedCentral Chen Y, Yang S, Zhou H, et al. PRDX2 promotes the proliferation and metastasis of non-small cell lung cancer in vitro and in vivo. Biomed Res Int. 2020;2020:8359860.PubMedPubMedCentral
39.
Zurück zum Zitat Wang G, Zhong WC, Bi YH, et al. The prognosis of peroxiredoxin family in breast cancer. Cancer Manage Res. 2019;11:9685–99.CrossRef Wang G, Zhong WC, Bi YH, et al. The prognosis of peroxiredoxin family in breast cancer. Cancer Manage Res. 2019;11:9685–99.CrossRef
40.
Zurück zum Zitat Kurono S, Kaneko Y, Matsuura N, et al. Identification of potential breast cancer markers in nipple discharge by protein profile analysis using two-dimensional nano-liquid chromatography/nanoelectrospray ionization-mass spectrometry. Proteomics Clin Appl. 2016;10(5):605–13.PubMedCrossRef Kurono S, Kaneko Y, Matsuura N, et al. Identification of potential breast cancer markers in nipple discharge by protein profile analysis using two-dimensional nano-liquid chromatography/nanoelectrospray ionization-mass spectrometry. Proteomics Clin Appl. 2016;10(5):605–13.PubMedCrossRef
41.
Zurück zum Zitat Stresing V, Baltziskueta E, Rubio N, et al. Peroxiredoxin 2 specifically regulates the oxidative and metabolic stress response of human metastatic breast cancer cells in lungs. Oncogene. 2013;32(6):724–35.PubMedCrossRef Stresing V, Baltziskueta E, Rubio N, et al. Peroxiredoxin 2 specifically regulates the oxidative and metabolic stress response of human metastatic breast cancer cells in lungs. Oncogene. 2013;32(6):724–35.PubMedCrossRef
42.
Zurück zum Zitat Liu FJ, Wang XB, Cao AG. Screening and functional analysis of a differential protein profile of human breast cancer. Oncol Lett. 2014;7(6):1851–6.PubMedPubMedCentralCrossRef Liu FJ, Wang XB, Cao AG. Screening and functional analysis of a differential protein profile of human breast cancer. Oncol Lett. 2014;7(6):1851–6.PubMedPubMedCentralCrossRef
43.
Zurück zum Zitat O’Leary PC, Terrile M, Bajor M, et al. Peroxiredoxin-1 protects estrogen receptor α from oxidative stress-induced suppression and is a protein biomarker of favorable prognosis in breast cancer. Breast Cancer Res. 2014;16(4):R79.PubMedPubMedCentralCrossRef O’Leary PC, Terrile M, Bajor M, et al. Peroxiredoxin-1 protects estrogen receptor α from oxidative stress-induced suppression and is a protein biomarker of favorable prognosis in breast cancer. Breast Cancer Res. 2014;16(4):R79.PubMedPubMedCentralCrossRef
44.
45.
Zurück zum Zitat Cooper J, Giancotti FG. Integrin signaling in cancer: mechanotransduction, stemness, epithelial plasticity, and therapeutic resistance. Cancer Cell. 2019;35(3):347–67.PubMedPubMedCentralCrossRef Cooper J, Giancotti FG. Integrin signaling in cancer: mechanotransduction, stemness, epithelial plasticity, and therapeutic resistance. Cancer Cell. 2019;35(3):347–67.PubMedPubMedCentralCrossRef
46.
Zurück zum Zitat Sung JS, Kang CW, Kang S, et al. ITGB4-mediated metabolic reprogramming of cancer-associated fibroblasts. Oncogene. 2020;39(3):664–76.PubMedCrossRef Sung JS, Kang CW, Kang S, et al. ITGB4-mediated metabolic reprogramming of cancer-associated fibroblasts. Oncogene. 2020;39(3):664–76.PubMedCrossRef
47.
Zurück zum Zitat Alimirzaie S, Bagherzadeh M, Akbari MR. Liquid biopsy in breast cancer: a comprehensive review. Clin Genet. 2019;95(6):643–60.PubMedCrossRef Alimirzaie S, Bagherzadeh M, Akbari MR. Liquid biopsy in breast cancer: a comprehensive review. Clin Genet. 2019;95(6):643–60.PubMedCrossRef
48.
Zurück zum Zitat Poulet G, Massias J, Taly V. Liquid biopsy: general concepts. Acta Cytol. 2019;63(6):449–55.PubMedCrossRef Poulet G, Massias J, Taly V. Liquid biopsy: general concepts. Acta Cytol. 2019;63(6):449–55.PubMedCrossRef
Metadaten
Titel
Study on the Relationship Between Differentially Expressed Proteins in Breast Cancer and Lymph Node Metastasis
verfasst von
Yu-Lu Sun
Yi-Xin Zhao
Yi-Nan Guan
Xin You
Yin Zhang
Meng Zhang
Hong-Yan Wu
Wei-Jie Zhang
Yong-Zhong Yao
Publikationsdatum
09.07.2023
Verlag
Springer Healthcare
Erschienen in
Advances in Therapy / Ausgabe 9/2023
Print ISSN: 0741-238X
Elektronische ISSN: 1865-8652
DOI
https://doi.org/10.1007/s12325-023-02588-w

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