Clinicopathological significance of PTPN12 expression in human breast cancer

Abstract

Protein tyrosine phosphatase non-receptor type 12 (PTPN12) is a recently identified tumor suppressor gene (TSG) that is frequently compromised in human triple-negative breast cancer. In the present study, we investigated the expression of PTPN12 protein by patients with breast cancer in a Chinese population and the relationship between PTPN12 expression levels and patient clinicopathological features and prognosis. Additionally, we explored the underlying down-regulation mechanism from the perspective of an epigenetic alteration. We examined PTPN12 mRNA expression in five breast cancer cell lines using semi-quantitative reverse-transcription PCR, and detected PTPN12 protein expression using immunohistochemistry in 150 primary invasive breast cancer cases and paired adjacent non-tumor tissues. Methylation-specific PCR was performed to analyze the promoter CpG island methylation status of PTPN12. PTPN12 was significantly down-regulated in breast cancer cases (48/150) compared to adjacent noncancerous tissues (17/150; P < 0.05). Furthermore, low expression of PTPN12 showed a significant positive correlation with tumor size (P = 0.047), lymph node metastasis (P = 0.001), distant metastasis (P = 0.009), histological grade (P = 0.012), and survival time (P = 0.019). Additionally, promoter CpG island hypermethylation occurs more frequently in breast cancer cases and breast cancer cell lines with low PTPN12 expression. Our findings suggest that PTPN12 is potentially a methylation-silenced TSG for breast cancer that may play an important role in breast carcinogenesis and could potentially serve as an independent prognostic factor for invasive breast cancer patients.

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

“…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.…”

“…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.…”

“…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.…”

“…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.…”

“…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.…”