Genetic alterations that are frequently seen in cancers include mutation, copy number loss/deletion, and copy number amplification. Gain-of-function mutations can increase the activity of an oncogene, and loss-of-function mutations may silence a tumor suppressor gene. Of the 21 PTPRs, 20 are mutated in multiple cancers, per The Cancer Genome Atlas (TCGA) data (summarized in Figure 1 ). Mutation appears to be the most common mechanism by which PTPRs are genetically modified when compared with copy number amplification or loss.

PTPRT is the most frequently mutated PTPR in human cancers. Wang et al.[13] reported that PTPRT was mutated in 27% of colorectal cancers (CRCs), 17% of gastric cancers, and 18% of lung cancers. They tested the functional consequences of 5 mutations in the catalytic domains of PTPRT and all 5 showed reduced phosphatase activity compared with wild-type PTPRT, indicating that these are loss-of-function mutations[13]. PTPRT mutation has also been reported in other cancers including head and neck squamous cell carcinoma (HNSCC)[14], acute myeloid leukemia[15], and T-cell large granular lymphocytic[16]. Functional analysis of PTPRT mutation in HNSCC revealed that normal function, signal transducer and activator of transcription 3 (STAT3) dephosphorylation, was abrogated for the mutant protein[17].

PTPRD is the second most commonly mutated PTPR across all human cancers. PTPRD mutation has been reported in cutaneous squamous cell carcinoma[18], glioblastoma multiforme (GBM)[19], melanoma[19], CRC[20], HNSCC[14], and lung cancer[21,22]. Functional studies of PTPRD mutation in neuroblastoma, melanoma, and GBM showed that mutation inactivated the function of PTPRD and that cancer cells harboring PTPRD mutations displayed decreased viability, thus suggesting PTPRD acts as a tumor suppressor in these cancers[19,23,24]. Wang et al.[13] also reported 6 (3%) PTPRF mutations in CRCs, 1 (9%) in lung cancer, and 1 (9%) in breast cancer. PTPRF mutation was also reported in HNSCC[14].

Behjati et al.[25] reported 14 PTPRB mutations in 10 of the 39 angiosarcomas studied. In tumors that were secondary and/or had MYC amplification, which is a radiation-associated biomarker of secondary angiosarcoma, the PTPRB mutation rate was up to 45% (10 of 22 cases). PTPRB inhibits angiogenesis, and inactivating mutations of PTPRB are considered driver events in angiosarcoma.

Copy number loss/deletion is common in cancers. Homozygous deletion usually contributes to loss of function of tumor suppressor genes. Many PTPRs negatively regulate cell proliferation, migration, and invasion, and homozygous deletion of these PTPRs may contribute to carcinogenesis. One of the most frequently deleted PTPRs is PTPRD. Homozygous or heterozygous loss of this gene has been reported in cutaneous squamous cell carcinoma[18,26], GBM[19,24], lung cancer[21,27], metastatic melanoma[28,29], neuroblastoma[30], squamous cell carcinoma of the vulva[31], hepatocellular carcinoma[32], and laryngeal squamous cell carcinoma[33] In addition, PTPRF deletion was reported in pheochromocytomas[34]. Down-regulation of PTPRF, considered a tumor suppressor in many cancers, was reported in liver cancer, gastric cancer, and CRC[35].

Promoter methylation is an epigenetic mechanism of regulating gene expression. Tumor suppressors are often silenced by promoter hypermethylation in cancer. Promoter methylation is also an important mechanism for PTPR inactivation in cancer. PTPRG is hypermethylated in multiple cancers including breast cancer[36], gastric cancer[37], nasopharyngeal carcinoma[38], Lynch syndrome CRC[39], childhood acute lymphoblastic leukemia[40], and cutaneous T-cell lymphoma[41]. PTPRG expression is negatively correlated with methylation, and when treated with methylation-suppressive agents like 5-aza-2′-deoxycytidine, PTPRG expression can be recovered[37,41]. A study of childhood acute lymphoblastic leukemia suggested that PTPRG methylation is induced by Ras mutations[40]

Promoter hypermethylation is also the primary mechanism of PTPRO dysregulation. PTPRO hypermethylation has been reported in hepatocellular carcinoma[42,43] colon cancer[44], lung cancer[45], and chronic lymphocytic leukemia[46]. You et al.[47] explored the potential of PTPRO as a biomarker in esophageal squamous cell carcinoma. They found PTPRO methylation in 75.0% (27 of 36) of solid tumors and 36.1%o (13 of 36) of matched peripheral blood samples, whereas no PTPRO methylation was observed in normal peripheral blood from 10 healthy subjects, suggesting PTPRO methylation is an epigenetic biomarker for noninvasive diagnosis of esophageal squamous cell carcinoma[47]. A study of breast cancer showed that PTPRO methylation was associated with lymph node involvement (P = 0.014), poorly differentiated histology (P = 0.037), depth of invasion (P = 0.004), and HER2 amplification (P = 0.001)[48]. PTPRO methylation was detected in 54% (53 of 98) of breast tumors and 34% (33 of 98) of matched peripheral blood samples from patients with breast cancer but in none of the normal peripheral blood samples from 30 healthy individuals[48]. Taken together, PTPRO methylation may represent a biomarker for noninvasive diagnosis and a prognostic factor in breast cancer.

Other PTPRs reported to be hypermethylated in cancer include PTPRD, PTPRF, PTPRJ, PTPRM, PTPRR, PTPRT, and PTPRZ1. In particular, PTPRD was found to be methylated in CRC, breast cancer, HNSCC, and GBM[24]. PTPRF hypermethylation is associated with phenobarbital-induced liver tumorigenesis[49], whereas PTPRJ hypermethylation was induced by microduplications in 2 patients with early-onset CRC[50]. Moreover, Laczmanska et al.[51] reported hypermethylation of PTPRM, PTPRR, PTPRT, and PTPRZ1 in sporadic CRC compared to non-cancer people.

Copy number amplification generally leads to gene overexpression and protein activation and is a common genetic alteration of oncogenes. Several PTPR genes, including PTPRC, PTPRR, and PTPRQ, are reportedly amplified in human cancers. PTPRC has the highest proportion of copy number amplifications among the PTPR genes, based on data for all cancers in the TCGA database. More specifically, PTPRC is amplified in 4.1% (212 of 5,130) of tumor samples across 16 cancers including 11.2% (108 of 962) of breast cancer samples and 13.6% (27 of 199) of liver cancer samples. PTPRQ and PTPRR amplifications were detected in a respective 8.7% (13 of 150) and 17.3% (26 of 150) of sarcoma samples in the TCGA repository. Furthermore, in samples in the TCGA repository, melanomas, lung adenocarcinomas, and sarcomas with PTPRR copy number amplifications have higher PTPRR mRNA levels than samples without copy number amplifications (Figure 2 ).

PTPRA copy gains have also been reported for some cancers. Junnila et al.[52] conducted an array-based analysis of gene expression and copy number levels using gastric cancer samples and then validated the results using the affinity capture-based transcript analysis (TRAC assay) and real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR). In their study, PTPRA copy number gain was detected in 5 of 13 primary gastric tumors and 3 of 7 gastric cell lines, and PTPRA overexpression was associated with copy number gain. Ardini et al.[53] reported PTPRA overexpression in 29% of breast cancers and found that high expression of PTPRA was associated with low tumor grade and positive estrogen receptor status. Furthermore, PTPRA overexpression in breast cancer cells inhibited cell growth, causing accumulation of cells in G₀ or G₁ phase[53].

Other PTPR genes that gain copies in cancer include PTPRF and PTPRH. PTPRF amplification was reported in a small cell lung cancer cell line and has also been observed in liver cancer[18,54]. PTPRH is also overexpressed in CRC[55]. Seo et al.[55] found no PTPRH expression in normal colon tissue but detected overexpression in 11.8% (2 of 17) of adenoma samples and 40% (19 of 48) of adenocarcinoma samples, suggesting overexpression of PTPRH may occur late in CRC tumorigenesis. Overall, the functional consequences of PTPR gene amplification are not well understood.

In summary, PTPR dysregulation in cancer occurs through several mechanisms. These include mutation, which is the most common mechanism; deletion and promoter methylation, which cause PTPR inactivation; and gene amplification, though the functional consequences and role of this mechanism require further study.

PTPRs play important roles in controlling cell signaling. Thus, dysregulation of PTPRs leads to signaling alterations.

Few drugs available to date directly target PTPRs. Several studies have investigated the clinical implication of PTPRs in the setting of cancer treatment. PTPRC is reportedly related to response to radiotherapy in the NCI-60 cancer cell collection[78] A recent report describes a 7-gene signature that predicts relapse and survival for early stage cervical carcinoma, namely PTPRF, ubiquitin-like 3 (UBL3), fibroblast growth factor 3 (FGF3), BMI1 proto-oncogene, polycomb ring finger (BMI1), platelet-derived growth factor receptor, alpha polypeptide (PDGFRA), replication factor C (activator 1) 4 (RFC4), and nucleolar protein 7 (NOL7)[79]. Recurrence-free survival was worse for patients with the signature compared with those without[79]. Notably, because PTPRF controls β-catenin signaling, the PTPRF extracellular domain was studied and confirmed as a novel plasma or tissue-based biomarker in prostate cancer[80].

PTPRF inhibitors are currently in development. Yang et al.[81] used a high-throughput screening assay to identify potential inhibitors of the PTPRF D1 and found that 1 of the 8 candidates showed specificity to PTPRF and was an effective inhibitor. Ajay et al.[82] used in silico assays, including pharmacophore mapping and 3D database searching, followed by SADMET-based virtual screening, docking analysis, and toxicity studies, and discovered 8 nontoxic PTPRF inhibitors. PTPRJ’s tumor suppressor role has been investigated in many human cancers including breast cancer[83], pancreatic cancer[84], and colon cancer[85]. Paduano et al.[86] identified from a phage display library a PTPRJ agonist peptide that binds and activates PTPRJ, leading to reduced MAPK phosphorylation, increased protein level of cell cycle inhibitor p27^Kip1, reduced proliferation, and increased apoptosis. Ortuso et al.[87] also discovered a PTPRJ agonist peptide, PTPRJ-pep19.4, and determined that the peptide inhibited in vitro tube formation, ERK1/2 phosphorylation, and proliferation in breast cancer cells but had no effect on primary normal human mammary endothelial cells.

Although there is limited clinical data on drugs that directly target PTPRs, PTPRs have been investigated as biomarkers for treatment or prognosis in different cancers. In addition, PTPR inhibitors and agonists are under development. Challenges in the development of PTPR-targeted therapies include the homology of PTPR catalytic domains[12] and the susceptibility of the active site of most PTPRs to oxidation. Further research is needed on the effect of current and emerging drugs in vivo.

In conclusion, PTPRs are a group of PTPs that share great structural similarity and play key roles in cell signaling. Alterations of these phosphatases, whether by mutation, deletion, amplification, or promoter methylation, are reported to cause aberrations in crucial cellular pathways related to proliferation, apoptosis, survival, migration, and invasion, suggesting these PTPRs are critical components in carcinogenesis. Therefore, efforts to determine how best to target PTPRs are warranted.