Bio-Pathological Functions of Posttranslational Modifications of Histological Biomarkers in Breast Cancer
Abstract
:1. Introduction
2. PTMs of Transcription Factors in Breast Cancer
2.1. ERα
2.2. PR
2.3. AR
2.4. p53
2.5. Transcription Factors Involved in Epithelial–Mesenchymal Transition
3. PTMs of Proliferation Marker Ki-67
4. PTMs of Plasma Membrane Proteins
4.1. HER2
4.2. Cell Adhesion Proteins
4.3. Other Proteins
5. Role of Histone Modifications in BC
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Hormone Receptors | Role | PTMs | Modifying Enzymes | PTM Sites | Effects of PTMs |
---|---|---|---|---|---|
Estrogen receptor alpha (ERα encoded by ESR1 gene) | nuclear receptor; transcription factor involved in cell proliferation, differentiation, and homeostasis; related to risk of BC, EC, and OC [77]; expressed in 70% of BC cases [41] | phosphorylation | c-Src kinase and ERK1/2 signaling pathways [77] | Ser118/167 [77]; Tyr537 [80,81] | alteration of ERα function (chromatin interaction, gene expression, BC growth, morphology, migration, invasion, and response to endocrine therapy) [77]; ERα phosphorylation by Src regulates its hormone-dependent nuclear export and cell cycle progression in BC cells [80] |
RAS-RAF-MAPK cascade [103] | Ser118 [103] | ER activation [103] | |||
acetylation | lysine acetyltransferases p300/CBP [104] | Lys266/268 | enhances E2-responsive genes transcription and signaling in BC [104,105] | ||
methylation | PRMT1 | Arg260 [85] | regulates ERα/PR cross-talk and activates a signaling complex in aggressive human BC [106] | ||
ubiquitination | ubiquitin ligases (CHIP, E3 ubiquitin-protein ligase MDM2, and E6AP) | K/Lys48 | degradation of ERα in UPS, changes in ERα function [82] | ||
deubiquitintion | deubiquitinases USP7 [41], USP1 [107], USP15 [40], USP14 [108], MINDY1 [109] | K/Lys48-linked ubiquitination | stabilizes ERα/prevents ERα degradation in BC and promotes BC progression in ERα+ BC [40,41] and EC [108], inhibits ERα K48-linked poly-ubiquitination [107] | ||
SUMOylation | SUMO1 [110] | SUMOylated lysines are located in the hinge region of ERα [110] | regulates ERα-dependent transcription in MCF7 BC cell line [110]; full anti-estrogenicity in the absence of accelerated receptor turnover [111] | ||
S-palmitoylation | palmitoylacyltransferases ZDHHC-7 ZHHHC-21 for sex steroid hormones | Cys447 | induces ERα localization to the plasma membrane and ERα-CAV1 interaction, enabling rapid E2 signaling for cell proliferation by ERK/MAPK, PI3K/AKT activation [67] | ||
Progesterone receptor (PR) | nuclear receptor; transcription factor; modulates ERα action in BC; activates cytosolic signaling pathways; upregulated target gene of ER; prognostic biomarker in BC, especially in HR+ BC [88,112]; PR-A is involved in cell adhesion, morphology, invasiveness and metastasis, resistance to apoptosis and tamoxifen; PR-B is required for mammary gland development and expansion [113] | phosphorylation | MAPK CDK2 PKA CK2 EGFR-induced phosphorylation/ERK-mediated, c-Src [112,114] | Ser294/345 [112,115]; Ser190/294/554/676 [116]; Ser191A [117] | regulates PR cell cycle and growth-promoting target genes [112]; activates PR hormone-dependent transcription [116]; PR phosphorylation targets it for ubiquitination and proteasomal destruction in cytosol [114] |
acetylation | p300 acetyltransferase | Lys183 | enhances PR-dependent initiation and reinitiation process via accelerated binding of its direct target genes; enhances Ser294 phosphorylation levels and PR activity, suppressing SUMOylation of PR [88] | ||
methylation | PRMT1 | Arg637 | stabilizes PR and accelerates its recycling and transcriptional activity; methylate ERαArg260, involved in ERα/PR cross talk [106] | ||
ubiquitination | PR phosphorylation via EGFR pathway leads to PR ubiquitination [114] | EC cells undergo loss of PR and do not respond to progestin therapy [114] | |||
SUMOylation/ deSUMOylation | SENP1 deSUMOylates PRA | SUMOylation attenuates PR activity on all target genes [113] | |||
palmitoylation | palmitoylacyltransferases ZDHHC-7 ZHHHC-21 for sex steroid hormones | a small fraction of the PR is palmitoylated and anchored to the cell membrane (mbPR), into a complex with ERα [118] | mbPR, upon progestin exposure, activates the Src/RAS/ERK kinase pathway, leading to phosphorylation of nPR by the ERK signaling pathway, leading to intracellular PR phosphorylation, gene regulation, and entry into cell cycle in the absence of detectable intracellular progestin [118] | ||
Androgen receptor (AR) | ligand-dependent/ligand-independent nuclear transcription factor, detected in 90% of primary BC, and 75% of metastasis [90]; prognostic and predictive biomarker in BC [44], involved in transcription, cellular proliferation, apoptosis in prostate cells [119] | phosphorylation | ERK1/2 and CDK1 [90] | increased on Ser213/650 in primary ER-negative BC, ductal carcinomas and metastases, compared to benign tissue [44]; Ser515 [92] | role in signal transduction; predictive value in BC prognosis [44] |
PI3K/AKT signaling [120] | Ser 213/791 | AKT is an activator of AR required for HER2 signaling to androgen-independent survival and growth of PC cells [120] | |||
Ser210/790 | AKT suppresses androgen-induced apoptosis by phosphorylating and inhibiting AR [121] | ||||
Ser16/81/256/308/424/650/94 in COS1 fibroblast-like cells and LNCaP cells [122] | analysis of cross-talk between growth factor signaling and androgen in prostate development, physiology, and cancer [122] | ||||
acetylation | KATs (CBP, P300, PCAF, TIP60, MOF, HBO1 ARD1) [119] | plays an important role in directing its cellular activities, modulating its stability, nuclear localization, and transcriptional activity [119] |
Transcription Factors | Role | PTMs | Modifying Enzymes | PTM Sites | Effects of PTMs |
---|---|---|---|---|---|
TWIST1 | regulator in embryonic development; implicated in tumor initiation, stemness, angiogenesis, spreading, and chemoresistance; promotes EMT in BC [139] | phosphorylation | MAPKs, JNK, ERK1/2, p38 | Ser68 | induces TWIST stabilization, EMT, invasiveness, metastasis in BC [140] |
AKT1 | Ser42/123, Thr121 | sustains β-TRCP-mediated TWIST1 ubiquitination and degradation; suppresses EMT; AKT1 inhibition stabilizes TWIST1 and enhances EMT in BC cells [141] | |||
SMAD3 | phosphorylation | MAPKs, CDKs, GSK3β | enhances or suppresses TGF-β signaling involved in apoptosis, growth arrest, differentiation, and EMT [73] | ||
Zinc finger E-box binding homeobox 1/2 (ZEB1/2) | frequently expressed in carcinomas, being involved in normal development and tumor metastasis [142] | phosphorylation | IGF1/MEK/ERK pathways; PKC | Thr867 hr851, Ser852, Ser853 | ZEB downregulation/transcriptional repression of ZEB1 [16] |
autophosphorylation | ATM hyperactivation | Ser585 | ZEB1 upregulation in radioresistant BC cells | ||
SNAIL/SNAI1 transcriptional repressor 1 | plays a role in the control of EMT and fibroblast activation [155] | phosphorylation | PAK1 | Ser246 | induces SNAIL activation and accumulation in the nucleus; promotes EMT [143] |
PI3K | Ser246 | increased SNAIL activation [156] | |||
PKD1 | Ser11 | nuclear export (destabilization) of SNAIL; reduces its transcriptional repressive activity, favors its ubiquitination and degradation and suppresses EMT [145] | |||
PKA, CK2 | Ser11/92 | SNAIL stability [157] | |||
GSK3β | Ser92/96/100/104 | SNAIL localization in cytoplasm; β-TRCP-mediated ubiquitination and proteasomal degradation [144,146] | |||
LATS2 | Thr203 | increases SNAIL nucleolar retention and activation [148] | |||
ERK2 | Ser82/104 | increases SNAIL nuclear accumulation and activation; suppresses E-cadherin; induces EMT [147] | |||
CK1 | Ser104/107 | mediates subsequent phosphorylation by GSK3β of S100/96/92, followed by TRCP-mediated ubiquitination and proteasomal degradation | |||
monoubiquitination | ubiquitin-editing enzyme A2 | K296, K234, K235 | monoubiquitinated SNAIL has a reduced affinity for GSK3β enzyme; stabilizes in nucleus and escape from degradation by GSK3β-mediated degradation [138] | ||
O-GlcNAc glycation | Ser112 | increases SNAIL stability by suppressing its degradation; disrupts CK1-mediated phosphorylation at S104/107, inhibiting GSK3β-mediated degradation [158] | |||
SLUG/SNAIL2 (encoded by SNAI2 gene) | has a zinc finger domain with transcriptional repressor activity [138] | phosphorylation | PAK4 | Ser158/254 | increases transcriptional activity and stabilization as a repressor of the CDH1 promoter in PC and accelerates cancer progression [159] |
GATA3 binding protein 3 (GATA3) | overexpressed in BC; involved in mammary gland development; biomarker for diagnosing BC; tumor suppressor in BC; regulates BC progression depending on cellular context [160] | function modulated by PTMs: acetylation | acetylated by acetyltransferase CBP at K119; deacetylated by HDAC1, HDAC2, HDAC3 | inhibits cell migration and invasion in lung adenocarcinoma, downregulating EMT-related transcription factors (SLUG, ZEB1, and ZEB2) [152] | |
methylation | Arg261 | regulates transactivation of the Il5 gene in T helper 2 (Th2) cells [161] | |||
progestin-induces GATA3 phosphorylation | Ser308 | induces its proteasome-mediated degradation, decreasing GATA3 levels in BC cells upon PR activation for progestin stimulation of in vitro cell proliferation and in vivo tumor growth [160] | |||
SRY-box transcription factor 2 (SOX2), octamer-binding transcription factor 4 (OCT4), Krűppel-like factor 4 (KLF4), c-MYC | involved in the generation of induced pluripotent stem cells (iPSCs) cells by reprogramming adult cells [153] | acetylation | PKB/AKT, p300 | stabilizes KLF4 by inactivating GSK3 [153] |
Classical Biomarkers | Role | PTMs | Modifying Enzymes | PTMs Sites | Effects of PTMs |
---|---|---|---|---|---|
Human epidermal growth factor receptor 2 (HER2/ErbB2 encoded by ERBB2 gene) | transmembrane glycoprotein with tyrosine kinase activity, overexpressed in 20–25% of BC [168] | phosphorylation | Y877 | in HER2-negative BC cell lines, makes HER2 recognizable by trastuzumab that decreases cell proliferation in HER2-/pHER2+ tumors as in HER2-positive BC cell lines [168,169] | |
neddylation | NEDD8 and NAE1 | neddylation inhibits HER2 degradation and promotes BC progression; inhibition of neddylation promotes HER2 degradation by improving its ubiquitination [170] | |||
Epidermal growth factor receptor (EGFR/ErbB1/ HER1) | mbEGFR glycoprotein can be internalized in the nucleus of the cell, acting in gene transcription, increasing proliferation, and favoring resistance to chemotherapy [171]; also identified as mtEGFR [27]; half of cases of TNBC and IBC overexpress EGFR that regulates EMT, migration, and invasion [176] | palmitoylation of mtEGFR [27] | promotes mitochondrial fusion and cell survival [27] | ||
phosphorylation | MEK1/2, ERK1/2 | Tyr1068 | |||
transphosphorylation | Src | Y845 other: Y992/1045/1068/1173 | leads to autophosphorylation and kinase activity for Ras/MAPK, PI3/AKT, and JAK-STAT3/5 [177] | ||
Y1045 | regulates EGFR ubiquitination and degradation [177] | ||||
acetylation | CBP acetyltransferase | affects its Tyr phosphorylation, inducing cancer cell resistance to HDAC inhibitors [178] | |||
ubiquitination and neddylation | c-Cbl ubiquitin ligase, ubiquitin-like molecule NEDD8 | induces lysosomal degradation; desensitizes growth-factor-activated receptor tyrosine kinase [179] |
Other Biomarkers | Role | PTMs | Modifying Enzymes | PTMs Sites | Effects of PTMs |
---|---|---|---|---|---|
Epithelial cell adhesion molecule (EpCAM) | surface protein; biomarker for epithelial tumors and CTCs; upregulated in solid epithelial cancers and stem cells; plays a role in cell adhesion, migration, proliferation, and differentiation [207] | deglycosylation | promotes apoptosis, downregulating Bcl-2 and upregulating Bax and caspase-3 through the ERK1/2 and c-Jun N-terminal kinase mitogen-activated protein kinase signaling pathways [35] | ||
O-linked glycosylation | Thr171, Thr172 | ||||
N-linked glycosylation | Asn74, Asn111, Asn198 | Asn198 is essential for stability maintenance of EpCAM; affects expression level and the molecule lifespan in the plasma membrane [208] | |||
Integrin β1 (ITGβ1) | cell adhesion glycoproteins that connect ECM to the cytoskeleton, involved in cancer progression, cell motility, adhesion, migration, proliferation, differentiation, and chemotherapy resistance [209] | α2,6 sialylation | β-galactosamide α-2,6-sialyltranferase I (ST6Gal-I) | plays critical roles in integrin activation [186]; regulator of cell adhesion and contributes to invasion of BC cells to ECM [195]; integrins are highly α2,6 sialylated on the MDA-MB-231 BC cell line but not on MCF7 BC cells [195]; in human colon tumors, sialylation of ITGβ1 blocks cell adhesion to GAL3 and protects cells against GAL3-induced apoptosis [210] | |
N-glycosylation | 12 potential N-glycosylation sites, including 7–8, 9–12 | ITGβ1 activation positively regulates cell migration, critical for PPIs with other cell membrane proteins (syndecan 4, EGFR) [186] | |||
Integrin β4 (ITGβ4) | transmembrane adhesion molecule; plays a role in invasion, proliferation, EMT, and angiogenesis; putative tumor marker [196] | phosphorylation by EGFR/Src-signaling | enhances malignant potential of BC [72] | ||
palmitoylation | catalyzed by ZDHHC3 | promotes invasive BC cell migration [26] | |||
Scribble (SCRIB) | cell junction and tumor-suppressor protein with a key role in maintaining polarity of epithelial cells; overexpressed and mislocated in human cancers, being involved in the regulation of Hippo pathway in BC cells [173] | palmitoylation | important for SCRIB membrane trafficking, cell polarity, and tumor suppression, emphasizing the importance of palmitoylation for cell polarity and tumorigenesis [173]. | ||
Caveolin 1 (CAV1) | membrane-associated scaffolding protein that acts as a tumor suppressor in early stages of cancer and promoter of metastasis; downregulated in human tumors, cancer cell lines and oncogene-transformed cells [211] | phosphorylation by Src tyrosine kinase mediated by RACK1 | RACK1 and Src silencing enhances drug sensitivity in MDR cells [74] | ||
Clusterin (CLU1)/apolipoprotein J (APOJ) | glycoprotein/chaperone involved in apoptosis, cell cycle regulation and DNA repair [199]; activity depends on its degree of glycosylation [201] | fucosylation | plays a role in BC progression via proangiogenic cytokines and TNF-α production by intratumoral macrophages [200] | ||
Programmed cell death ligand 1 (PD-L1) | transmembrane protein overexpressed in many cancers, known for its oncogenic function exerted by activation of Wnt/β-catenin pathway [203,204] | palmitoylation | affects its stability; targeting PD-L1 palmitoylation sensitized tumor cells to T-cell killing and inhibited tumor growth [203]. |
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Neagu, A.-N.; Josan, C.-L.; Jayaweera, T.M.; Morrissiey, H.; Johnson, K.R.; Darie, C.C. Bio-Pathological Functions of Posttranslational Modifications of Histological Biomarkers in Breast Cancer. Molecules 2024, 29, 4156. https://doi.org/10.3390/molecules29174156
Neagu A-N, Josan C-L, Jayaweera TM, Morrissiey H, Johnson KR, Darie CC. Bio-Pathological Functions of Posttranslational Modifications of Histological Biomarkers in Breast Cancer. Molecules. 2024; 29(17):4156. https://doi.org/10.3390/molecules29174156
Chicago/Turabian StyleNeagu, Anca-Narcisa, Claudiu-Laurentiu Josan, Taniya M. Jayaweera, Hailey Morrissiey, Kaya R. Johnson, and Costel C. Darie. 2024. "Bio-Pathological Functions of Posttranslational Modifications of Histological Biomarkers in Breast Cancer" Molecules 29, no. 17: 4156. https://doi.org/10.3390/molecules29174156