Proteomics-Based Identification of Dysregulated Proteins in Breast Cancer
Abstract
:1. Introduction
2. Proteomics-Based Investigation of Dysregulated Steroid Receptors and HER2
3. Proteomics-Based Investigation of Transcriptional and Translational Dysregulation in BC
4. Proteomics-Based Identification of Dysregulated Proteins Involved in BC EMT, Invasion and Metastasis
5. Proteomics-Based Identification of Dysregulated Proteins Involved in Intermediary Metabolism Reprogramming in BC Cells
Protein | Gene Name | Biological and Pathological Role in BC | Methods of Identification | Status in BC | Potential Clinical Use |
---|---|---|---|---|---|
Steroid receptors and HER2 | |||||
Estrogen receptors | ER isoforms: ERα & ERβ | Nuclear receptors/TFs that regulates transcription of estrogen target genes [67]; ERα is a promoter of cell proliferation/tumorigenesis in BC, and ERβ suppresses cell proliferation [68] | IHC [116], MALDI-TOF MS [67], LC-SRM MS [27]; multiplex IHC-MALDI-MSI (MALDI-IHC) [17] | More than 70% of all BC are ERα [117] | Diagnostic biomarkers, classification of BC subtypes [67] |
nLC/ESI-MS/MS; MALDI-MS/MS (MSn) [70] | PTMs and PPI modulate activity: ubiquitination [117]; phosphorylation [70] | Tamoxifen resistance [72] | |||
Progesterone receptors | PR isoforms: PRA & PRB | TFs that modulate ERα action in BC [118]; exhibits both activatory and repressive effect on gene transcription [119] | IHC [116]; LC-SRM MS [27]; multiplex IHC-MALDI-MSI (MALDI-IHC) [17] | Association between ERα/PR induces cell proliferation and tumor growth [120] | Predictive biomarker [121], prognostic and predictive biomarker of response to endocrine therapy [118] |
Androgen receptor | AR | Nuclear TF that mediates the biological effects of androgens; tumor suppressor in ER+ BC and inducer of tumor progression in ER- BC, including HER2+ and TNBC [68], it has a crucial role in BC pathology and progression [122] | IHC [123], PRM targeted proteomic [124] | Expressed in 70–90% of the BCs [122]; upregulated in luminal A & B subtypes of BC and a subset of TNBC; positive immunostaining was associated with smaller tumor size [123] | Possible prognostic biomarker [123]; potential therapeutic target in AR+ BC patients [122] |
Human epidermal growth factor receptor 2 | HER2/neu, c-erbB2 | Membrane tyrosine kinase and oncogene [76]; regulates cell growth, survival, differentiation and proliferation [74] | IHC, FISH, CISH, SISH [76]; MALDI-MSI [77], LC-MS/MS+SRM assay+FISH+IHC [125]; LC-SRM MS [27]; multiplex IHC-MALDI-MSI (MALDI-IHC) [17] | Overexpressed in 20–30% of BC [76] | Predictive and prognostic biomarker; treatment target [76]; poor prognosis and increased likehood of metastasis especially in node-positive BC [126] |
Transcription and translation regulation | |||||
Core binding factor subunit beta | CBFB | Translation regulation in cytoplasm and transcription regulation in the nucleus [78] | IHC, IF, immunoblotting, MS [78] | Highly mutated in solid tumors, including BC [78], mutations mainly occur in HR+/HER2- BC [127] | Putative prognostic biomarker in HR+/HER2- BC [127] |
Catenin beta 1 | CTNNB1 | Transcriptional regulation in the Wnt signaling pathway and cell adhesion molecule by linking cadherins to the actin cytoskeleton [92]; downregulation inhibited cell proliferation, migration, and invasion and induced apoptosis in RCC [128] | LC-MS/MS [56]; IHC [129] | Key role in most cancers as an oncogene [128]; β-catenin/Wnt pathway activation is preferentially found in TN-BL breast carcinomas [130] | Prognostic biomarker [131]; poor clinical outcome in BC [130] |
Histone H1 | H1 (seven somatic proteoforms [132]) | Chromatin organization and transcriptional regulation; knock-down in BC results in altered gene expression, proliferation, and IFN response [133] | Immunoblotting, IHC, LC-MS, LC-MS/MS [132] | H1 showed PTMs in BC cells [133] | Putative biomarker of proliferation BC cells [132] |
EMT, cytoskeleton reorganization, cell adhesion, ECM, invasion and metastasis | |||||
Vimentin | VIM | EMT; intermediate filament family protein; in IDC is associated with low ER, low PR, increased basement membrane invasiveness, and resistance to BC chemotherapy [134] | IHC [134], IF [135]; LC-MS for detection of phosphorylated isoform that increases mobility in cancer cells [87]; MALDI-TOF MS/MS for detection of methylated isoform [89] and interaction VIM-garlic phytochemical with anti-metastatic activity [91] | Overexpressed in BC, especially in BLBC [89] | Mesenchymal marker, poor prognostic factor of BC [134] |
Epithelial (E)-cadherin | CDH1 | EMT; adhesion molecule of the epithelial adherens junction; dual role in BC: putative tumor suppressor [136] or promotor of metastasis and invasiveness [137] | IHC [137,138], IF [135]; 2D-DIGE and MS [139] | Downregulated in BC [140] | Phenotypic marker; biomarker of tumor subtypes [136]; prognostic biomarker for patients with lymph node metastasis and TNBC [141] |
Filamin A | FLNA | EMT; actin cross-linking protein, involved in regulation of BRCA1 expression in BC [142] | IHC [142]; LC-MS/MS [56] | Upregulated in BC, especially in myoepithelial cells [142] | Putative prognostic biomarker [142] |
Pleckstrin homology domain-containing family G member 2 | PLEKHG2 | Actin cytoskeleton reorganization and transcriptional regulation, regulation of cell morphology [28] | MALDI-MSI, LC-MALDI-MS/MS [28] | Phosphorylated in TNBC [28] | Prognostic biomarker [28] |
SRY-related high-mobility-group (HMG) box 11 | SOX11 | Transcription factor and embryonic mammary epithelial marker associated with mesenchymal state and embryonic phenotype of BC cells [135]; involved in BC growth, migration, and invasion, regulating the BLBCs phenotype [28] | WB, IF [135]; IHC [143], MALDI-MSI, LC-MS/MS [28] | Upregulated in BLBC [144] | Prognostic biomarker [28] for BC with elevated risk of distant metastases and poor outcome [135], therapeutic target [28]; ER negative DCIS SOX11+ tumor cells metastasize to brain and bone at greater frequency than in lungs [135] |
Collagen type I alpha 1 chain | COL1A1 | EMT; promotes BC metastasis [98]; upregulation is a risk factor for radiation-associated secondary diseases in BC [145] | IHC [98], MALDI-MSI, LC-MALDI-MS/MS [28] | Upregulated in invasive BC (IDC) [[28,97] | Prognostic biomarker [28], poor survival in ER+ BC, potential therapeutic target [98] |
Collagen type I alpha 2 chain | COL1A2 | EMT; ECM assembly; upregulation is a risk factor for radiation-associated secondary diseases in BC [145] | MALDI-MSI, LC-MALDI-MS/MS [28] | Upregulated in invasive BC [28] | Prognostic biomarker [28] |
Cytokeratins | CKs | IFs [146]; CK+ cells are enriched in cancer stem cell proprieties [92] | IHC [146]; multiplex IHC-MALDI-MSI (MALDI-IHC) [17] | CK 5/6 upregulated in ER+ BC and BLBC [147] | Adjuncts in diagnosis, classification and prognostication of BC [146] |
Intermediary metabolism reprogramming | |||||
Fatty acid synthase | FASN | FAM; enhances malignant progression [148], migration, metastasis [149], proliferation, drug resistance, and apoptosis [150]; inhibition reduces cell proliferation, suppresses migration and invasion and induces apoptosis [151] | LC-MS/MS [56], MALDI-TOF/TOF MS/MS [126]; IHC [150] | Overexpressed in cancer cells [148]; highly expressed in different sex hormone-related malignant tumors, positive expression in TNBC correlated with lymph node metastasis and stage [150] | Prognostic biomarker in TNBC [150] |
Triose-phosphate isomerase | TPI1 | Glycolysis; promotes tumor development and progression of BC in tissue and cell lines, proliferation, metastasis, activates PI3K/Akt/mTOR, regulates EMT [152] | WB, IHC, IF [152]; MALDI-TOF/TOF MS/MS [126] | Upregulated in multiple cancers [152] | Therapeutic target for BC [152] |
Alpha-enolase | ENO1 | Cell growth, hypoxia tolerance, autoimmune activities, glycolysis pathway [153] | WB [154], IHC [155], LC-MS/MS [156]; MALDI-TOF/TOF MS/MS [126] | Upregulated in BC [153,154] | Prognostic biomarker [155,157] |
Phosphoglycerate kinase 1 | PGK1 | Glycolysis, hypoxia; cancer progression, metastases; invasion promoter, regulates HIF-1α-mediated EMT [158] | MALDI-TOF/TOF MS/MS [126] | Overexpressed in BC [158] | Poor prognosis, potential survival biomarker in BC [158] |
Cell cycle, cellular division, mitotic spindle, cell proliferation | |||||
Jumping translocation breakpoint protein/prostate androgen regulated protein | JTB/PAR | Dual role: tumor suppressor or oncogene; involved in cell proliferation, tumorigenesis, genomic instability [159] | WB, immunoprecipitation, IF [159] | Overexpressed in many cancers, including BC [159] | Putative target for therapeutic intervention [159] |
Beta-tubulin | TUBB | Carcinogenesis, metastasis [160] | LC-MS/MS [56] | Upregulated in BC tissue [160] | Potential prognostic biomarker for worse prognosis in ERα+ and better prognosis in ERα- BC [160] |
Proliferation marker protein Ki-67 | MKI67 | Proliferation-associated nuclear antigen involved in cell proliferation and growth, migration, invasion, tumor progression, maintenance of stem cell characteristics [161] | IHC [162,163]; LC-MS/MS [56] | Overexpressed in cancer cells [164] | Marker of cell proliferation, prognostic and predictive biomarker in invasive BC [165,166] |
Aminoimidazole-4- carboxamide ribonucleotide | ATIC | Cell proliferation [28] | MALDI MSI [28] | Upregulated in TNBC [28] | Putative prognostic biomarker [28] and therapeutic target in BC resistant to tamoxifen [28,167] |
Mutant tumor suppressor p53 protein | TP53/mtp53 | Driver oncogene [168], transcription factor involved in cell cycle; mtp53-related proteome targets cholesterol biosynthesis, DNA replication and repair pathways [168] | IHC [169,170], SILAC coupled to MS/MS [168] | The most frequently mutated gene in invasive BC; mutated in 30–35% of all BCs, and 80% in TNBC [171] | Potential biomarker and therapeutic target for BC patients, especially for TNBC [171] |
6. Proteomics-Based Investigation of PTMs and PPIs in BC
7. Proteomics-Based Investigation of Dysregulated Proteins in Diverse Liquid Biopsies/Body Fluids
Body Fluids | Proteomics-Based Techniques | Applications in BC |
---|---|---|
Blood/plasma/serum | SELDI-TOF MS, MALDI-TOF/TOF MS | Identification of panels of serum biomarkers for BC [49] |
2DE, MALDI-TOF MS | Serum proteomic differences between patients with MBC and healthy controls [204] | |
LC-MS/MS | BC grading and subtyping, identification of biomarkers for cell growth, ECM and cell-to-cell communication, energy metabolism and gene transcription, cell death and cancer development, transcription regulation, tumorigenesis and invasion, redox balance, and EMT [205]; secretome of BC CAFs [207]; exosomal BC proteome [211]; exosomal phosphoproteome [213] | |
Proximal fluid proteomics/nipple aspirate fluid (NAF)/dried NAF spots on Guthrie cards | MALDI-TOF MS [214], LC-MS/MS [66], SELDI-TOF MS [215] | Early BC detection; biomarkers discovery in BC [216] |
nLC-ESI-Q-TOF MS | Early BC screening and subtype classification [219] | |
Milk | LC-MS/MS | Differential protein pattern between breastfeeding mothers with BC compared with healthy women; identification of putative biomarkers for BC [42]; detection of αS1-casein [221]; EVs proteome identification [224] |
Urine | LC-MS/MS | Detection of overexpressed proteins in DCIS samples, early invasive and metastatic BC [32]; progressive changes during BC development in rat model [34] |
MALDI-TOF/TOF, LC-MS/MS | Detection of urinary proteome alterations in HER2 enriched BC [33] | |
Tears | SELDI-TOF MS [40], MALDI-TOF/TOF [38], LC-MS/MS [39] | Identification of differential biomarker profiles for BC patients compared to healthy controls; identification of dysregulated proteins involved in ECM remodeling [39], host immune system pathways, metabolic regulation [38] |
Saliva | LC-MS/MS | Identification of biomarkers for DCIS or HER2/neu positive or negative BC [36] |
nLC-Q-TOF MS | Differential immune landscape, molecular transport and signaling pathways between FA and IDC [239] | |
MALDI-TOF MS, MALDI-TOF/TOF MS [240] | Identification of new BC biomarkers [240] | |
SELDI-TOF MS [231], ESI-TOF MS, MALDI-TOF MS [233], ESI-Orbitrap MS, ESI-Q-TOF MS [234] | Panels of biomarkers for accurate discrimination between BC stages [235] or between BC patients and healthy controls [236] |
8. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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PTMs | References | Proteins | Function and Roles in BC |
---|---|---|---|
Phosphorylation | [175] | histone H1 isoforms [132] | Putative biomarker of proliferation BC cells [132] |
YWHAH | BC cell migration [181] | ||
PKA/BAD | Stemness and survival of BCSCs [182] | ||
ACAP4 | Phosphorylated ezrin and phosphorylated ACAP4 interacts to induce membrane fusion of intracellular tubule-vesicles with the apical membrane; cancer progression and metastasis [199], cell migration, polarity, vesicle trafficking and tumorigenesis, regulation of cell adhesion [200] | ||
ERα | Critical in development and progression of BC [70] | ||
MZF1 [180] | Development of aggressive BC, control of genes involved in EMT, lysosome-mediated invasion/metastasis [201] | ||
TUBG1 | Phosphorylation deficiency impairs centrosome construction and microtubules nucleation [186] | ||
CTTN | Phosphorylated CTTN may play a critical role in promoting breast cancer cell mobility and invasion via actin polymerization [185] | ||
IκBα | Phosphorylation of NF-κB inhibitor alpha is involved in NF-κB TF activity, regulating apoptosis and necroptosis in BC cells [179] | ||
FAK autophosphorylation | Activation of FAK-SRC signaling complex that trigger pathways involved in cancer cell migration, invasion, proliferation, death and malignant tumor progression [184] | ||
Glycosylation | [177] | membrane proteins [188], i.e., PD-L1 | Potential therapeutic strategies to increase cancer immune therapy efficacy [189] |
Acetylation | [173] | nuclear proteins [187], ACAP4 [183] | BC cell migration and invasion [183] |
Ubiquitination | [178] | PD-L1 | Potential therapeutic strategies to increase cancer immune therapy efficacy [189] |
SUMOylation | [172] | MZF1 | Transcriptional activation or inactivation [201] |
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Neagu, A.-N.; Jayathirtha, M.; Whitham, D.; Mutsengi, P.; Sullivan, I.; Petre, B.A.; Darie, C.C. Proteomics-Based Identification of Dysregulated Proteins in Breast Cancer. Proteomes 2022, 10, 35. https://doi.org/10.3390/proteomes10040035
Neagu A-N, Jayathirtha M, Whitham D, Mutsengi P, Sullivan I, Petre BA, Darie CC. Proteomics-Based Identification of Dysregulated Proteins in Breast Cancer. Proteomes. 2022; 10(4):35. https://doi.org/10.3390/proteomes10040035
Chicago/Turabian StyleNeagu, Anca-Narcisa, Madhuri Jayathirtha, Danielle Whitham, Panashe Mutsengi, Isabelle Sullivan, Brindusa Alina Petre, and Costel C. Darie. 2022. "Proteomics-Based Identification of Dysregulated Proteins in Breast Cancer" Proteomes 10, no. 4: 35. https://doi.org/10.3390/proteomes10040035