PTPN12 promotes resistance to oxidative stress and supports tumorigenesis by regulating FOXO signaling.

It is well known that protein tyrosine phosphatases (PTPs) that become oxidized due to exposure to reactive oxygen species (ROS) undergo a conformational change and are inactivated. However, whether PTPs can actively regulate ROS levels in order to prevent PTP inhibition has yet to be investigated. Here, we demonstrate that PTP non-receptor type 12 (PTPN12) protects cells against aberrant ROS accumulation and death induced by oxidative stress. Murine embryonic fibroblasts (MEFs) deficient in PTPN12 underwent increased ROS-induced apoptosis under conditions of antioxidant depletion. Cells lacking PTPN12 also showed defective activation of FOXO1/3a, transcription factors required for the upregulation of several antioxidant genes. PTPN12-mediated regulation of ROS appeared to be mediated by phosphoinositide-dependent kinase-1 (PDK1), which was hyperstimulated in the absence of PTPN12. As tight regulation of ROS to sustain survival is a key feature of cancer cells, we examined PTPN12 levels in tumors from a cohort of breast cancer patients. Patients whose tumors showed high levels of PTPN12 transcripts had a significantly poorer prognosis. Analysis of tissues from patients with various breast cancer subtypes revealed that more triple-negative breast cancers, the most aggressive breast cancer subtype, showed high PTPN12 expression than any other subtype. Furthermore, both human breast cancer cells and mouse mammary epithelial tumor cells engineered to lack PTPN12 exhibited reduced tumorigenic and metastatic potential in vivo that correlated with their elevated ROS levels. The involvement of PTPN12 in the antioxidant response of breast cancer cells suggests that PTPN12 may represent a novel therapeutic target for this disease.

The roles of PTEN in development, physiology and tumorigenesis in mouse models: a tissue-by-tissue survey.

In 1997, PTEN (phosphatase and tensin homologue deleted on chromosome 10, 10q23.3) was identified as an important tumor suppressor gene that is inactivated in a wide variety of human cancers. Ever since, PTEN's function has been extensively studied, and huge progress has been made in understanding PTEN's role in normal physiology and disease. In this review, we will systematically summarize the important data that have been gained from gene inactivation studies in mice and will put these data into physiological context using a tissue-by-tissue approach. We will cover mice exhibiting complete and constitutive inactivation of Pten as well as a large number of strains in which Pten has been conditionally deleted in specific tissues. We hope to highlight not only the tumor suppressive function of Pten but also its roles in embryogenesis and in the maintenance of the normal physiological functions of many organ systems.

Acute neuronopathic Gaucher disease complicated by fatal gastrointestinal bleeding.

Gaucher disease, a rare lysosomal storage disease caused by deficiency of glucocerebrosidase, may present with gastrointestinal bleeding. We report about an 11-month-old boy suffering from acute neuronopathic Gaucher disease who died after massive gastrointestinal bleeding. A gastric ulcer was found as the sole bleeding source. The gastric mucosa showed marked infiltration with Gaucher cells, in particular around the ulcer. Alterations of the gastrointestinal mucosa offer a new explanation for gastrointestinal bleedings in this disease.

Supratentorial meningeal melanocytoma mimicking a convexity meningioma.

OBJECTIVE AND IMPORTANCE: Meningeal melanocytomas are rare benign neuro-ectodermal tumors arising from melanocytic cells in the leptomeninges. These leptomeningeal melanocytes are found at highest density underneath the brain stem and along the upper cervical spinal cord. Thus, most reported cases of meningeal melanocytomas are located in the posterior fossa and the spinal cord, respectively. CLINICAL PRESENTATION: We report on the rare case of a 55-year-old male patient with a large supratentorial meningeal melanocytoma mimicking a convexity meningioma and a smaller, similarly dura based lesion in the posterior fossa. INTERVENTION: Tumor control to date was achieved by surgery of the large lesion and radiosurgery of the small lesion. CONCLUSION: Complete tumor resection may be advantageous and second or recurrent lesions may be managed by repeat surgery or stereotactic radiosurgery.

Genetic alteration and expression of the phosphoinositol-3-kinase/Akt pathway genes PIK3CA and PIKE in human glioblastomas.

Glioblastomas frequently carry genetic alterations resulting in an aberrant activation of the phosphoinositol-3-kinase (Pi3k)/protein kinase B (Akt) signalling pathway, including most notably phosphatase and tensin homolog (PTEN) mutation, epidermal growth factor receptor (EGFR) amplification and rearrangement, as well as carboxyl-terminal modulator protein (CTMP) hypermethylation [Knobbe et al., (2004) Hypermethylation and transcriptional downregulation of the carboxyl-terminal modulator protein gene in glioblastomas. J Natl Cancer Institute, 96, 483-486]. Here, we investigated two further Pi3k/Akt pathway genes, namely PIK3CA (3q26.3) and phosphatidylinositol-3-kinase enhancer (PIKE) (CENTG1, 12q14), for genetic alteration and aberrant expression in a series of 97 primary glioblastomas. Single strand conformation polymorphism (SSCP) analysis of PIK3CA revealed somatic mutations in five tumours (5%). Twelve glioblastomas (12%) showed amplification of PIKE with invariable co-amplification of the adjacent CDK4 gene. All tumours with PIKE amplification as well as the vast majority of glioblastomas without amplification demonstrated increased expression of PIKE-A but not PIKE-S/L transcripts as compared with non-neoplastic brain tissue. Taken together, our data support an important role of PIK3CA and PIKE gene aberrations in the molecular pathogenesis of primary glioblastomas.

Somatic mutations in the PTCH, SMOH, SUFUH and TP53 genes in sporadic basal cell carcinomas.

BACKGROUND: Basal cell carcinoma (BCC) of the skin is the most common human cancer. The genetic alterations underlying BCC development are only partly understood. OBJECTIVES: To investigate further the molecular genetics of sporadic BCCs, we performed mutation analyses of 10 skin cancer-associated genes in 42 tumours. METHODS: Single-strand conformational polymorphism analysis followed by DNA sequencing was used to screen for mutations in the sonic hedgehog pathway genes PTCH, SMOH, SUFUH and GLI1, in the TP53 tumour suppressor gene, and in the proto-oncogenes NRAS, KRAS, HRAS, BRAF and CTNNB1. Microsatellite markers flanking the PTCH, SUFUH and TP53 loci at 9q22, 10q24 and 17p13, respectively, were studied for loss of heterozygosity (LOH). RESULTS: PTCH mutations were found in 28 of 42 tumours (67%). Microsatellite analysis revealed LOH on 9q22 in 20 of 38 tumours investigated (53%), including 14 tumours with and six tumours without PTCH mutations. SMOH mutations were identified in four of the 42 BCCs (10%) while two tumours demonstrated mutations in SUFUH, including one missense mutation and one silent mutation. None of the BCCs showed LOH at markers flanking the SUFUH locus. Seventeen BCCs (40%) carried TP53 mutations, with only three tumours showing evidence of biallelic TP53 inactivation. TP53 mutations were present in BCCs with and without mutations in PTCH, SMOH or SUFUH. Interestingly, 72% of the TP53 alterations were presumably ultraviolet (UV)-induced transition mutations. In contrast, only 40% of the PTCH and SMOH alterations corresponded to UV signature mutations. No mutations were identified in GLI1, NRAS, KRAS, HRAS, BRAF or CTNNB1. CONCLUSIONS: Our data confirm the importance of PTCH, SMOH and TP53 mutations in the pathogenesis of sporadic BCCs. SUFUH alterations are restricted to individual cases while the other investigated genes do not appear to be important targets for mutations in BCCs.