Emerging potential of ubiquitin-specific proteases and ubiquitin-specific proteases inhibitors in breast cancer treatment

Table 1 Ubiquitin-specific proteases studied in breast cancer

USPs	Expression	Potential role in breast cancer	Signal pathway
USP1	Upregulated	Tumor promoter	KPNA2, ERα signaling, Hippo signaling pathway, TGF-β signaling[20-23]
USP4	Upregulated	Tumor suppressor	PDCD4, circBMPR2, PAK5-DNPEP pathway, Relaxin/TGF-β1/Smad2/MMP-9 signaling, TGF-β signaling[24-28]
USP7	Upregulated	Tumor promoter	PHF8,DNA repair, Aurora-A kinase, ECT2[29-34]
USP9X	Upregulated	Tumor promoter, Tumor suppressor	CEP131, Hippo Pathway, Notch signaling, Cyclin D1,Wnt signaling, TRAIL, YAP1[35,37,38,40,41,45,46]
USP11	Upregulated	Tumor promoter	TGFβ signaling, DNA damage, XIAP[47-49]
USP14	Upregulated	Tumor promoter	CyclinB1, Wnt/β-catenin and PI3K/AKT pathways, cell cycle[53,54]
USP15	Upregulated	Tumor promoter	DNA repair, ERα signaling[65,66]
USP18	Upregulated	Tumor promoter	AKT/Skp2 pathway[68]
USP20	Upregulated	Tumor promoter	SNAI2[69]
USP22	Upregulated	Tumor promoter	c-Myc, Hh pathway[57,58]
USP28	Upregulated	Tumor suppressor	HIF-independent pathway, LSD1[71,72]
USP32	Upregulated	Tumor promoter	Unknown[73]
USP33	Upregulated	Tumor suppressor	Slit-Robo signaling[74]
USP37	Upregulated	Tumor promoter	Stemness, epithelial-mesenchymal transition[60]
USP39	Upregulated	Tumor promoter	G0/G1-phase arrest, CHEK2[62,63]

USPs: Ubiquitin-specific peptidases; KPNA2: Karyopherin subunit α-2; ER: Estrogen receptor; TGF-β: Transforming growth factor-β; PDCD4: Programmed cell death 4 protein; circBMPR2: Bone morphogenetic protein 2; PAK5: P21-activated kinase; DNPEP:Aspartyl aminopeptidase; MMP-9: Matrix metallopeptidase 9;Smad2: Small mothers against decapentaplegic 2; PHF8: Plant homeodomain finger protein 8; DNA: Deoxyribonucleic acid; ECT2: Epithelial cell transforming 2; CEP131: Centrosomal protein 131; TRAIL: TNF-related apoptosis-inducing ligand; YAP1: Yes-associated protein 1; XIAP: X-linked inhibitor of apoptosis protein; PI3K: Phosphoinositide 3-kinase; AKT: Protein kinase B; Skp2: S-phase kinase-associatedprotein 2; SNAI2: Snail family transcriptional repressor 2; Hh: Hedgehog; HIF: Hypoxia inducible factor-1; LSD1: Human lysine specific demethylases l; CHEK2: checkpoint kinase 2.

Table 2 Reported ubiquitin-specific peptidases inhibitors in breast cancer study

Target		Breast cancer subtype	Experiment	Pathways
USP1	Pimozide	ER negative BC, TNBC	In vitro; In vivo	Cell cycle, AKT signaling pathway, EMT, MMP-9, vimentin, STAT3[76,78,79]
	Trifluoperazin	TNBC	In vitro; In vivo	G0/G1 arrest, cyclinD1/CDK4, cyclinE/CDK2[80]
	Rottlerin	ER positive BC, TNBC, CSCs	In vitro	NFκB, cyclin D-1, p38 MAPK, AMPK, proteasome inhibition, Skp2[81-84]
	ML323	BC	In vitro; In vivo	KPNA2[20]
USP2	6-TG	BRCA2-defective PARP inhibitor-resistant BC, BRCA1-mutant BC, TNBC	In vitro; In vivo	DNA repair, PI3K-AKT, apoptosis pathway, lncRNA-miRNA-mRNA ceRNA network, DNMT1[85,87,88,90]
	ML364	ER-positive BC	In vitro	Endocytic degradation[91]
USP7	Costunolide	metastatic TNBC, BC	In vitro	NF-κB signaling, cell cycle regulation, c-Myc/p53, AKT/14-3-3 pathway, p38MAPK pathways[92-95]
USP7/47	P5091	BC	In vitro	EMT[96]
USP14	b-AP15	ER positive BC, TNBC	In vitro; In vivo	Autophagy, ERα signaling[98,99]
	IU1	AR-positive BC	In vitro; In vivo	Wnt/β-catenin, PI3K/AKT pathways[55]
	Auranofin	ER positive BC, TNBC	In vitro; In vivo	PTGR1 expression, ERK1/2-MYC, p38 MAPK signaling pathway, mitochondrial apoptosis[100-102]
USP9x	WP1130	ER-negative BC	In vitro	Mcl-1[43]

USPs: Ubiquitin-specific peptidases; ER: Estrogen receptor; BC: Breast cancer; TNBC: Triple-negative breast cancer; AKT: Protein kinase B; EMT: Epithelial mesenchymal transition; MMP-9: Matrix metallopeptidase 9; STAT3: Signal transducerand activator of transcription 3; CDK: Cyclin-Dependent Kinase; NFκB: Nuclear factor kappa-B; MAPK: Mitogen-activated protein kinase; AMPK: Adenosine 5'-monophosphate (AMP)-activated protein kinase; Skp2: S-phase kinase-associatedprotein 2; KPNA2: Karyopherinα2; CSCs: Cancer stem cells; BRCA: Breast cancer 1; PARP: Poly (ADP-ribose) polymerase; DNA: Deoxyribonucleic acid; PI3K: Phosphoinositide 3-kinase; AKT: Protein kinase B; lncRNA: Long non-coding RNA; miRNA: MicroRNA; ceRNA: Competing endogenous RNA; DNMT1: DNA (cytosine-5-)-methyltransferase 1; AR: Androgen receptor; MAPK: Mitogen-activated protein kinase; PTGR1: Prostaglandin reductase 1; ERK1/2: Extracellular regulated protein kinases 2; Mcl-1: Myeloid cell leukemia-1.