Low Expression of Tyrosine-protein Phosphatase Nonreceptor Type 12 is Associated with Lymph Node Metastasis and Poor Prognosis in Operable Triple-negative Breast Cancer

Wu, Min; Hu, Pan; Gao, Jie; Wei, Wei Dong; Xiao, Xiang; Tang, Hai; Li, Xing; Ge, Qi; Jia, Wei Hua; Liu, Ren Bin; Xie, Xiao

doi:10.7314/apjcp.2013.14.1.287

Cited by 19 publications

(21 citation statements)

References 28 publications

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“…Combined, our findings suggest a possible mechanism by which loss of PTPN12 in humans would be associated with more aggressive breast cancer subtypes, such as TNBCs (14,16,17). We propose that loss of PTPN12 in breast cancer, which is initiated by oncogenic receptor PTKs (such as ErbB2), promotes tumor progression by shifting the profile of tumors toward that of more aggressive tumors.…”

Section: Discussionmentioning

confidence: 91%

“…The latter group found that PTPN12 RNA was more frequently elevated in TNBCs than other subtypes of human breast cancer. Others observed the opposite when PTPN12 protein expression was analyzed (14,16,17). In addition, Harris et al observed that shRNA-mediated downregulation of PTPN12 expression caused diminished tumorigenicity and metastatic potential in established breast cancer cell lines.…”

Section: Discussionmentioning

confidence: 93%

“…Heterozygous PTPN12-deficient mice had a phenotype intermediate between those of PTPN12-expressing and homozygous PTPN12-deficient mice, implying that the tumor-suppressing effect of PTPN12 was dose dependent. Thus, as suggested for hu- man breast cancer (14,16,17), PTPN12 is a suppressor of breast cancer development and progression in the MMTV-NIC model.…”

Section: Discussionmentioning

confidence: 99%

“…Lastly, they documented frequent loss of PTPN12 in human breast cancer cell lines and samples, as a result of point mutations, large deletions, altered microRNA expression, or reduced protein expression. These changes were more commonly seen in triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer.In support of the tumor suppressor role of PTPN12, at least two others groups also documented loss of PTPN12 protein in human breast cancer using immunohistochemistry or immunoblot analyses (16,17). This alteration was more common in TNBC.…”

mentioning

confidence: 98%

“…In support of the tumor suppressor role of PTPN12, at least two others groups also documented loss of PTPN12 protein in human breast cancer using immunohistochemistry or immunoblot analyses (16,17). This alteration was more common in TNBC.…”

mentioning

confidence: 98%

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Loss of PTPN12 Stimulates Progression of ErbB2-Dependent Breast Cancer by Enhancing Cell Survival, Migration, and Epithelial-to-Mesenchymal Transition

Davidson

Souza

et al. 2015

Molecular and Cellular Biology

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e PTPN12 is a cytoplasmic protein tyrosine phosphatase (PTP) reported to be a tumor suppressor in breast cancer, through its capacity to dephosphorylate oncogenic receptor protein tyrosine kinases (PTKs), such as ErbB2. However, the precise molecular and cellular impact of PTPN12 deficiency in breast cancer progression remains to be fully clarified. Here, we addressed this issue by examining the effect of PTPN12 deficiency on breast cancer progression in vivo, in a mouse model of ErbB2-dependent breast cancer using a conditional PTPN12-deficient mouse. Our studies showed that lack of PTPN12 in breast epithelial cells accelerated breast cancer development and lung metastases in vivo. PTPN12-deficient breast cancer cells displayed enhanced tyrosine phosphorylation of the adaptor Cas, the adaptor paxillin, and the kinase Pyk2. They exhibited no detectable increase in ErbB2 tyrosine phosphorylation. PTPN12-deficient cells were more resistant to anoikis and had augmented migratory and invasive properties. Enhanced migration was corrected by inhibiting Pyk2. PTPN12-deficient breast cancer cells also acquired partial features of epithelial-to-mesenchymal transition (EMT), a feature of more aggressive forms of breast cancer. Hence, loss of PTPN12 promoted tumor progression in a mouse model of breast cancer, supporting the notion that PTPN12 is a tumor suppressor in human breast cancer. This function was related to the ability of PTPN12 to suppress cell survival, migration, invasiveness, and EMT and to inhibit tyrosine phosphorylation of Cas, Pyk2, and paxillin. These findings enhance our understanding of the role and mechanism of action of PTPN12 in the control of breast cancer progression. P rotein tyrosine phosphatases (PTPs) play a key role in normal cellular processes, such as proliferation, migration, adhesion, differentiation, and immune cell activation (1-3). Depending on the phosphatase and the cell type, they also have the ability either to suppress or to promote malignant transformation (3). PTPN12, also referred to as PTP-PEST (PTP-proline, glutamic acid, serine, and threonine rich), is a cytoplasmic PTP expressed in a wide spectrum of cell types (4). Studies of PTPN12-deficient mice showed that PTPN12 is a critical positive regulator of migration and adhesion in embryonic fibroblasts, endothelial cells, T cells, macrophages, and dendritic cells (5-11). This function relates to the capacity of PTPN12 to dephosphorylate cytoskeletonassociated substrates such as protein tyrosine kinases (PTKs) Pyk2 and FAK or the adaptors Cas, paxillin, and PSTPIP-1. These substrates are components of the cellular machinery controlling migration and adhesion. PTPN12 can also regulate other substrates, including receptor PTKs, such as ErbB2 and the adaptor . Proteomic data suggested that the ability of PTPN12 to regulate Shc might be critical for conversion of Shc-dependent proliferative signals into migratory signals (15). Several PTPN12 substrates, and in particular, Cas, paxillin, and Shc, also directly associate with PTPN12....

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 98%

mentioning

confidence: 98%

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Loss of PTPN12 Stimulates Progression of ErbB2-Dependent Breast Cancer by Enhancing Cell Survival, Migration, and Epithelial-to-Mesenchymal Transition

Davidson

Souza

et al. 2015

Molecular and Cellular Biology

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PTPN12 inhibits oral squamous epithelial carcinoma cell proliferation and invasion and can be used as a prognostic marker

Tian

Song³

et al. 2013

Med Oncol

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Protein tyrosine phosphatase nonreceptor type 12 (PTPN12) has been recognized as a tumor suppressor gene that may inhibit tumor growth. However, PTPN12 expression in oral squamous carcinoma (OSCC) has not been studied. We showed reduced expression of PTPN12 in OSCC tissues. Decreased PTPN12 expression was significantly associated with clinical stage of the disease (P < 0.01). Moreover, reduction in PTPN12 correlated with the overactivation of STAT3. PTPRD negatively related to STAT3 phosphorylation (R = -0.535). Low expression of PTPN12 and high level of phosphorylation of STAT3 correlated with poor prognosis. Overexpression of PTPN12 inhibited proliferation and migration in OSCC cells. PTPN12 was associated with STAT3 and induced STAT3 dephosphorylation. Moreover, our results suggested that PTPN12 might function through binding and dephosphorylation of STAT3. Therefore, PTPN12 is a potential marker for prognosis of OSCC.

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The prognostic significance of tyrosine-protein phosphatase nonreceptor type 12 expression in nasopharyngeal carcinoma

Zhang

Chen

et al. 2015

Tumor Biol.

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Tyrosine-protein phosphatase nonreceptor type 12 (PTPN12) has been proposed to predict prognosis of various human cancers. However, the clinicopathologic and prognostic significance of PTPN12 expression in NPC has not yet been elucidated. The objective of this study was to investigate the clinicopathological and prognostic implication of PTPN12 in nasopharyngeal carcinoma (NPC) patients. Protein expression levels of PTPN12 were explored by semiquantitative immunohistochemical staining on archival formalin-fixed, paraffin-embedded pathological specimens consisting of 203 NPCs, and 40 normal nasopharyngeal mucosa tissues. Receiver operating characteristic (ROC) curve analysis was employed to determine the cutoff score of PTPN12 expression in NPCs. The PTPN12 immunohistochemical staining results were then correlated with various clinicopathological features and patients’ prognosis using various statistical models. Our results showed that decreased expression of PTPN12 was more frequently observed in NPC tissues compared with the normal nasopharyngeal mucosa. Further correlation analyses indicated that the decreased expression of PTPN12 was significantly associated with tumor T classification, N classification, distant metastasis, and clinical stage in NPCs (P < 0.05). Univariate analysis showed a significant association between the decreased expression of PTPN12 and adverse overall survival and disease-free survival (P < 0.05). More importantly, multivariate analysis identified the PTPN12 expression in NPC as an independent prognostic factor. The decrease expression of PTPN12 might be important in conferring a more aggressive behavior in NPC. Thus, PTPN12 expression may be used as a novel independent prognostic biomarker for patients with NPC.

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Low Expression of Tyrosine-protein Phosphatase Nonreceptor Type 12 is Associated with Lymph Node Metastasis and Poor Prognosis in Operable Triple-negative Breast Cancer

Cited by 19 publications

References 28 publications

Loss of PTPN12 Stimulates Progression of ErbB2-Dependent Breast Cancer by Enhancing Cell Survival, Migration, and Epithelial-to-Mesenchymal Transition

Loss of PTPN12 Stimulates Progression of ErbB2-Dependent Breast Cancer by Enhancing Cell Survival, Migration, and Epithelial-to-Mesenchymal Transition

PTPN12 inhibits oral squamous epithelial carcinoma cell proliferation and invasion and can be used as a prognostic marker

The prognostic significance of tyrosine-protein phosphatase nonreceptor type 12 expression in nasopharyngeal carcinoma

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