Frequent MYC coamplification and DNA hypomethylation of multiple genes on 8q in 8p11-p12-amplified breast carcinomas

Parris, Toshima Z.; Kovács, Anikó; Hajizadeh, Shahin; Nemes, Szilárd; Semaan, May; Levin, Michael; Karlsson, Per; Helou, Khalil

doi:10.1038/oncsis.2014.8

Cited by 64 publications

(65 citation statements)

References 55 publications

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“…In addition, we attempted to determine whether there was a correlation between MIM expression and any clinical variables. However this proved to be intractable due to the genomic location of MIM, close to the c-MYC gene (hg18), which is part of a genomic region commonly amplified in breast cancer samples [36]. …”

Section: Resultsmentioning

confidence: 99%

Missing-in-Metastasis regulates cell motility and invasion via PTPδ-mediated changes in SRC activity

Chaudhary

Lucito

Tonks

2014

Biochemical Journal

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Missing in Metastasis (MIM), also known as MTSS1, is a scaffold protein that is down-regulated in multiple metastatic cancer cell lines compared to non-metastatic counterparts. MIM regulates cytoskeletal dynamics and actin polymerization, and has been implicated in the control of cell motility and invasion. MIM has also been shown to bind to a receptor PTP, PTPδ, an interaction that may provide a link between tyrosine phosphorylation-dependent signaling and metastasis. We used shRNA-mediated gene silencing to investigate the consequences of loss of MIM on the migration and invasion of the MCF10A mammary epithelial cell model of breast cancer. We observed that suppression of MIM by RNAi enhanced migration and invasion of MCF10A cells, effects that were associated with increased levels of PTPδ. Furthermore, analysis of human clinical data indicated that PTPδ was elevated in breast cancer samples when compared to normal tissue. We demonstrated that the SRC protein tyrosine kinase is a direct substrate of PTPδ and, upon suppression of MIM, we observed changes in the phosphorylation status of SRC, in particular the inhibitory site (Tyr 527) was hypophosphorylated, whereas the activating autophosphorylation site (Tyr 416) was hyperphosphorylated. Thus, the absence of MIM led to PTPδ-mediated activation of SRC. Finally, the SRC inhibitor SU6656 counteracted the effects of MIM suppression on cell motility and invasion. This study illustrates that both SRC and PTPδ have the potential to be therapeutic targets for metastatic tumors associated with loss of MIM.

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Section: Resultsmentioning

confidence: 99%

Missing-in-Metastasis regulates cell motility and invasion via PTPδ-mediated changes in SRC activity

Chaudhary

Lucito

Tonks

2014

Biochemical Journal

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“…In addition, SMC4/condensin interacts with the genomic transcriptional insulator CTCF, and thus may be required for oncogenic gene silencing (48). SQLE is a cholesterol biosynthesis enzyme that has been implicated in several cancers other than prostate, and, interestingly, is located in the chromosome 8q24 Myc oncogene amplicon (49)(50)(51). SQLE knockdown had an impact in LNCaP-AR but not DU145 cells, which is likely reflective of the much more significant role of steroid hormone signaling in LNCaP-AR cells.…”

Section: Discussionmentioning

confidence: 99%

The Landscape of Prognostic Outlier Genes in High-Risk Prostate Cancer

Zhao

Evans

Kothari

et al. 2016

Clinical Cancer Research

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Purpose: There is a clear need to improve risk stratification and to identify novel therapeutic targets in aggressive prostate cancer. The goal of this study was to investigate genes with outlier expression with prognostic association in high-risk prostate cancer patients as potential biomarkers and drug targets.Experimental Design: We interrogated microarray gene expression data from prostatectomy samples from 545 high-risk prostate cancer patients with long-term follow-up (mean 13.4 years). Three independent clinical datasets totaling an additional 545 patients were used for validation. Novel prognostic outlier genes were interrogated for impact on oncogenic phenotypes in vitro using siRNA-based knockdown. Association with clinical outcomes and comparison with existing prognostic instruments was assessed with multivariable models using a prognostic outlier score.Results: Analysis of the discovery cohort identified 20 prognostic outlier genes. Three top prognostic outlier genes were novel prostate cancer genes; NVL, SMC4, or SQLE knockdown reduced migration and/or invasion and outlier expression was significantly associated with poor prognosis. Increased prognostic outlier score was significantly associated with poor prognosis independent of standard clinicopathologic variables. Finally, the prognostic outlier score prognostic association is independent of, and adds to existing genomic and clinical tools for prognostication in prostate cancer (Decipher, the cell-cycle progression signature, and CAPRA-S).Conclusions: To our knowledge, this study represents the first unbiased high-throughput investigation of prognostic outlier genes in prostate cancer and demonstrates the potential biomarker and therapeutic importance of this previously unstudied class of cancer genes.

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“…Dysregulation of SQLE has been observed in several cancer types, including breast cancer, lung cancer, and colorectal cancer [11][12][13][14][15]. However, the expression profile and the function of SQLE in hepatocellular carcinoma remain largely unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Dysregulation of SQLE in the cancer cells has been reported. Frequent Myc gene amplification and DNA hypomethylation of SQLE promoter were observed in aggressive breast cancer and indicated poor outcome [11]. Also, SQLE and other genes involved in cholesterol biosynthesis were important for the radioresistance in pancreatic cancer [12,13].…”

Section: Introductionmentioning

confidence: 99%

Squalene epoxidase (SQLE) promotes the growth and migration of the hepatocellular carcinoma cells

et al. 2015

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Hepatocellular carcinoma (HCC) is one of the most common malignancies with a poor response to chemotherapy. It is very important to identify novel therapeutic targets. Squalene epoxidase (SQLE), one of the rate-limiting enzymes in the cholesterol biosynthesis, recently has been found to be involved in the tumorigenesis. However, its expression profile and function in the progression of HCC remain largely unknown. Here, we found that the expression of SQLE was upregulated in the HCC tissues. Moreover, overexpression of SQLE in HCC cells promoted cell proliferation and migration, while downregulation of SQLE inhibited the tumorigenicity of HCC cells in vitro and in vivo. Mechanistically, SQLE positively regulated the ERK signaling. Taken together, our study suggests that SQLE is a promising therapeutic target in HCC.

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Frequent MYC coamplification and DNA hypomethylation of multiple genes on 8q in 8p11-p12-amplified breast carcinomas

Cited by 64 publications

References 55 publications

Missing-in-Metastasis regulates cell motility and invasion via PTPδ-mediated changes in SRC activity

Missing-in-Metastasis regulates cell motility and invasion via PTPδ-mediated changes in SRC activity

The Landscape of Prognostic Outlier Genes in High-Risk Prostate Cancer

Squalene epoxidase (SQLE) promotes the growth and migration of the hepatocellular carcinoma cells

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