Recurrent Hemizygous Deletions in Cancers May Optimize Proliferative Potential

Solimini, Nicole L.; Xu, Qikai; Mermel, Craig H.; Liang, Anna C.; Schlabach, Michael R.; Luo, Ji; Burrows, Anna E.; Anselmo, Anthony; Bredemeyer, Andrea L.; Li, Mamie Z.; Beroukhim, Rameen; Meyerson, Matthew; Elledge, Stephen J.

doi:10.1126/science.1219580

Cited by 182 publications

(182 citation statements)

References 33 publications

Supporting

Mentioning

166

Contrasting

Unclassified

Order By: Relevance

“…1A; Supplementary Table S5). We then asked whether downregulation of these genes increased cell proliferation, as this is one of the most commonly altered processes promoting tumorigenesis observed in tumors with mutations in TS genes (26). Downregulation of seven SB-identified candidate TS genes (ADNP, AP2B1, ARL6IP5, TOMM70A, ZC3H7A, ZCCHC7, and ZNF326) led to a >15% increase in cell proliferation with all three siRNAs tested, in each of the four cell lines assayed, suggesting a high probability of TS activity (Fig.…”

Section: Resultsmentioning

confidence: 99%

Identification of New Tumor Suppressor Genes in Triple-Negative Breast Cancer

et al. 2017

View full text Add to dashboard Cite

Although genomic sequencing has provided a better understating of the genetic landmarks in triple-negative breast cancer (TNBC), functional validation of candidate cancer genes (CCG) remains unsolved. In this study, we used a transposon mutagenesis strategy based on a two-step sleeping beauty (SB) forward genetic screen to identify and validate new tumor suppressors (TS) in this disease. We generated 120 siRNAs targeting 40 SB-identified candidate breast cancer TS genes and used them to downregulate expression of these genes in four human TNBC cell lines. Among CCG, whose SB-mediated genetic mutation resulted in increased cellular proliferation in all cell lines tested, the genes ADNP, AP2B1, TOMM70A, and ZNF326 showed TS activity in tumor xenograft studies. Subsequent studies showed that ZNF326 regulated expression of multiple epithelial-mesenchymal transition and cancer stem cell (CSC) pathway genes. It also modulated expression of TS genes involved in the regulation of migration and cellular invasion and was a direct transcriptional activator of genes that regulate CSC self-renewal. ZNF326 expression associated with TNBC patient survival, with ZNF326 protein levels showing a marked reduction in TNBC. Our validation of several new TS genes in TNBC demonstrate the utility of two-step forward genetic screens in mice and offer an invaluable tool to identify novel candidate therapeutic pathways and targets.

show abstract

Section: Resultsmentioning

confidence: 99%

Identification of New Tumor Suppressor Genes in Triple-Negative Breast Cancer

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Both hemizygous PSMC2 copy number loss and transcriptional repression of UBB might serve to optimize cell fitness by tuning protein fate in a way that stabilizes prosurvival proteins during tumorigenesis (33 To restrict the analysis to the human cells in the sample, results were normalized to human GAPDH by the ΔΔCT method. UBC levels were then normalized to the shNT-no-Dox sample.…”

Section: Discussionmentioning

confidence: 99%

Recurrent ubiquitin B silencing in gynecological cancers establishes dependence on ubiquitin C

Kedves¹,

Gleim²,

Liang³

et al. 2017

Journal of Clinical Investigation

View full text Add to dashboard Cite

“…Deletions at this locus routinely inactivate both cell-cycle regulators Stott et al 1998). Recent evidence also suggests that oncogenes and tumor suppressor genes (TSGs) are clustered, including several TSGs on 8p21-23 in hepatocellular carcinoma, three oncogenes (NKX2-1, NKX2-8, and PAX9) on 14q13 in lung cancer, two oncogenes (CCND1 and FGF19) on 11q13, and two oncogenes (BIRC2 and YAP1) on 11q22 in liver cancer (Zender et al 2006;Kendall et al 2007;Sawey et al 2011;Solimini et al 2012;Xue et al 2012). Similar to the results presented here, phenotypes induced by the manipulation of individual genes are relatively weak, whereas the concerted deregulation of entire cancer gene clusters result in more significant effects.…”

Section: Discussionmentioning

confidence: 99%

Systems consequences of amplicon formation in human breast cancer

et al. 2014

View full text Add to dashboard Cite

Chromosomal structural variations play an important role in determining the transcriptional landscape of human breast cancers. To assess the nature of these structural variations, we analyzed eight breast tumor samples with a focus on regions of gene amplification using mate-pair sequencing of long-insert genomic DNA with matched transcriptome profiling. We found that tandem duplications appear to be early events in tumor evolution, especially in the genesis of amplicons. In a detailed reconstruction of events on chromosome 17, we found large unpaired inversions and deletions connect a tandemly duplicated ERBB2 with neighboring 17q21.3 amplicons while simultaneously deleting the intervening BRCA1 tumor suppressor locus. This series of events appeared to be unusually common when examined in larger genomic data sets of breast cancers albeit using approaches with lesser resolution. Using siRNAs in breast cancer cell lines, we showed that the 17q21.3 amplicon harbored a significant number of weak oncogenes that appeared consistently coamplified in primary tumors. Down-regulation of BRCA1 expression augmented the cell proliferation in ERBB2-transfected human normal mammary epithelial cells. Coamplification of other functionally tested oncogenic elements in other breast tumors examined, such as RIPK2 and MYC on chromosome 8, also parallel these findings. Our analyses suggest that structural variations efficiently orchestrate the gain and loss of cancer gene cassettes that engage many oncogenic pathways simultaneously and that such oncogenic cassettes are favored during the evolution of a cancer.

show abstract

Recurrent Hemizygous Deletions in Cancers May Optimize Proliferative Potential

Cited by 182 publications

References 33 publications

Identification of New Tumor Suppressor Genes in Triple-Negative Breast Cancer

Identification of New Tumor Suppressor Genes in Triple-Negative Breast Cancer

Recurrent ubiquitin B silencing in gynecological cancers establishes dependence on ubiquitin C

Systems consequences of amplicon formation in human breast cancer

Contact Info

Product

Resources

About