PTEN dosage is essential for neurofibroma development and malignant transformation

Gregorian, Caroline; Nakashima, Jonathan; Dry, Sarah M.; Nghiemphu, Phioanh L.; Smith, Kate Barzan; Ao, Yan; Dang, Julie; Lawson, Gregory; Mellinghoff, Ingo K.; Mischel, Paul S.; Phelps, Michael E.; Parada, Luis F.; Liu, Xin; Sofroniew, Michael V.; Eilber, Fritz C.; Wu, Hong

doi:10.1073/pnas.0910398106

Cited by 104 publications

(85 citation statements)

References 45 publications

(55 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Silencing of the PTEN tumor suppressor has also been associated with increased glycolytic activity (43, 44) and is more common in basal-like breast cancer (45). The relationship between FDG-PET positivity and PI3K pathway activation in breast cancer warrants further study.…”

Section: Discussionmentioning

confidence: 99%

Multiplexed immunofluorescence delineates proteomic cancer cell states associated with metabolism

Sood¹,

Miller²,

Brogi³

et al. 2016

JCI Insight

Self Cite

View full text Add to dashboard Cite

The phenotypic diversity of cancer results from genetic and nongenetic factors. Most studies of cancer heterogeneity have focused on DNA alterations, as technologies for proteomic measurements in clinical specimen are currently less advanced. Here, we used a multiplexed immunofluorescence staining platform to measure the expression of 27 proteins at the single-cell level in formalin-fixed and paraffin-embedded samples from treatment-naive stage II/III human breast cancer. Unsupervised clustering of protein expression data from 638,577 tumor cells in 26 breast cancers identified 8 clusters of protein coexpression. In about one-third of breast cancers, over 95% of all neoplastic cells expressed a single protein coexpression cluster. The remaining tumors harbored tumor cells representing multiple protein coexpression clusters, either in a regional distribution or intermingled throughout the tumor. Tumor uptake of the radiotracer 18F-fluorodeoxyglucose was associated with protein expression clusters characterized by hormone receptor loss, PTEN alteration, and HER2 gene amplification. Our study demonstrates an approach to generate cellular heterogeneity metrics in routinely collected solid tumor specimens and integrate them with in vivo cancer phenotypes.

show abstract

Section: Discussionmentioning

confidence: 99%

Multiplexed immunofluorescence delineates proteomic cancer cell states associated with metabolism

Sood¹,

Miller²,

Brogi³

et al. 2016

JCI Insight

Self Cite

View full text Add to dashboard Cite

show abstract

“…For instance, loss of the phosphate and tensin homologue tumor suppressor, an inhibitor of the PI3K-Akt-TSC2-mTOR-S6 pathway, is evident in approximately 60% of MPNSTs. 48,49 Epigenetic repression of tumor suppressors also plays a role in MPNST pathogenesis, as demonstrated by the recent finding that expression of Ras association domain family member 1, isoform A (RASSF1A) is silenced in MPNSTs by DNA methylation. 50 The discovery of candidate oncogenes in MPNSTs was driven primarily by a search for therapeutic targets.…”

Section: Genomic Abnormalities Mediating Neurofibroma-mpnst Progressionmentioning

confidence: 99%

The Challenge of Cancer Genomics in Rare Nervous System Neoplasms

Carroll

2016

The American Journal of Pathology

View full text Add to dashboard Cite

Comprehensive genomic analyses of common nervous system cancers provide new insights into their pathogenesis, diagnosis, and treatment. Although analogous studies of rare nervous system tumors are needed, there are major barriers to performing such studies. Cross-species comparative oncogenomics, identifying driver mutations in mouse cancer models and validating them in human tumors, is a promising alternative. Although still in its infancy, this approach is being applied to malignant peripheral nerve sheath tumors (MPNSTs), rare Schwann cellederived malignancies that occur sporadically, after radiotherapy, and in neurofibromatosis type 1. Studies of human neurofibromatosis type 1eassociated tumors suggest that NF1 tumor suppressor loss in Schwann cells triggers cell-autonomous and intercellular changes, resulting in development of benign neurofibromas; subsequent neurofibroma-MPNST progression is caused by aberrant growth factor signaling and mutations affecting the p16 INK4A -cyclin D1-CDK4-Rb and p19 ARF -Mdm2-p53 cell cycle pathways. Mice with Nf1, Trp53, and/or Cdkn2a mutations that overexpress the Schwann cell mitogen neuregulin-1 or overexpress the epidermal growth factor receptor validate observations in human tumors and, to various degrees, model human tumorigenesis. Genomic analyses of MPNSTs arising in neuregulin-1 and epidermal growth factor receptor-overexpressing mice and forward genetic screens with Sleeping Beauty transposons implicate additional signaling cascades in MPNST pathogenesis. These studies confirm the utility of mouse models for MPNST driver gene discovery and provide new insights into the complexity of MPNST pathogenesis. (Am J Pathol 2016, 186: 464e477; http://dx

show abstract

“…For example, decreased levels of tumor suppressor genes, such as EGR1 and PTEN, have been associated with tumors such as sarcomas, colon tumors, and brain tumors (12)(13)(14)(15). On the basis of this general concept, we hypothesized that transcriptional perturbations in specific miRNA(s) observed across multiple tumor types regulate the levels of important tumor suppressors in these tumor types.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA miR-183 Functions as an Oncogene by Targeting the Transcription FactorEGR1and Promoting Tumor Cell Migration

2010

View full text Add to dashboard Cite

The transcription factor EGR1 is a tumor suppressor gene that is downregulated in many cancer types. Clinically, loss of EGR1 translates to increased tumor transformation and subsequent patient morbidity and mortality. In synovial sarcoma, the SS18-SSX fusion protein represses EGR1 expression through a direct association with the EGR1 promoter. However, the mechanism through which EGR1 becomes downregulated in other tumor types is unclear. Here, we report that EGR1 is regulated by microRNA (miR)-183 in multiple tumor types including synovial sarcoma, rhabdomyosarcoma (RMS), and colon cancer. Using an integrative network analysis, we identified that miR-183 is significantly overexpressed in these tumor types as well as in corresponding tumor cell lines. Bioinformatic analyses suggested that miR-183 could target EGR1 mRNA and this specific interaction was validated in vitro. miR-183 knockdown in synovial sarcoma, RMS, and colon cancer cell lines revealed deregulation of a miRNA network composed of miR-183-EGR1-PTEN in these tumors. Integrated miRNA-and mRNA-based genomic analyses indicated that miR-183 is an important contributor to cell migration in these tumor types and this result was functionally validated to be occurring via an EGR1-based mechanism. In conclusion, our findings have significant implications in the mechanisms underlying EGR1 regulation in cancers. miR-183 has a potential oncogenic role through the regulation of 2 tumor suppressor genes, EGR1 and PTEN, and the deregulation of this fundamental miRNA regulatory network may be central to many tumor types. Cancer Res; 70(23); 9570-80. Ó2010 AACR.

show abstract

PTEN dosage is essential for neurofibroma development and malignant transformation

Cited by 104 publications

References 45 publications

Multiplexed immunofluorescence delineates proteomic cancer cell states associated with metabolism

Multiplexed immunofluorescence delineates proteomic cancer cell states associated with metabolism

The Challenge of Cancer Genomics in Rare Nervous System Neoplasms

MicroRNA miR-183 Functions as an Oncogene by Targeting the Transcription FactorEGR1and Promoting Tumor Cell Migration

Contact Info

Product

Resources

About