Splicing dysregulation as a driver of breast cancer

Read, Abigail; Natrajan, Rachael

doi:10.1530/erc-18-0068

Cited by 32 publications

(29 citation statements)

References 93 publications

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“…Decades of research have revealed an array of dynamic regulatory networks that control each phase of gene expression (48,52,53). When these mechanisms fail, it can result in the development of numerous diseases, including cancer (51,(54)(55)(56). Understanding how different signaling events directly impact the initial phases of gene expression will provide new insight into the mechanisms of disease and identify new strategies for treatment.…”

Section: Discussionmentioning

confidence: 99%

Cell-free transcription in Xenopus egg extract

Barrows

Long

2019

Journal of Biological Chemistry

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Edited by John M. Denu Soluble extracts prepared from Xenopus eggs have been used extensively to study various aspects of cellular and developmental biology. During early egg development, transcription of the zygotic genome is suppressed. As a result, traditional extracts derived from unfertilized and early stage eggs possess little or no intrinsic transcriptional activity. In this study, we show that Xenopus nucleoplasmic extract (NPE) supports robust transcription of a chromatinized plasmid substrate. Although prepared from eggs in a transcriptionally inactive state, the process of making NPE resembles some aspects of egg fertilization and early embryo development that lead to transcriptional activation. With this system, we observed that promoter-dependent recruitment of transcription factors and RNA polymerase II leads to conventional patterns of divergent transcription and pre-mRNA processing, including intron splicing and 3 cleavage and polyadenylation. We also show that histone density controls transcription factor binding and RNA polymerase II activity, validating a mechanism proposed to regulate genome activation during development. Together, these results establish a new cell-free system to study the regulation, initiation, and processing of mRNA transcripts.

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Section: Discussionmentioning

confidence: 99%

Cell-free transcription in Xenopus egg extract

Barrows

Long

2019

Journal of Biological Chemistry

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“…Note that 95% of pre-mRNAs are alternatively spliced in humans,6 leading to at least 100,000 distinct proteins despite only 20,000 protein-coding genes 7. Once disorders, abnormal protein subtype will be formed and deregulate multiple biological processes, such as cell proliferation, differentiation, apoptosis, cycle, metabolism, invasion, migration and angiogenesis,8 and has been considered to be involved in the development of many kinds of tumors, including ovarian cancer,9 lung cancer,10 osteosarcoma,11 gastric cancer12 and breast cancer,13 and so on. In recent years, studies have found that PUF60, a splicing factor, is involved in the progression of several various kinds of tumors 14.…”

Section: Introductionmentioning

confidence: 99%

PUF60 accelerates the progression of breast cancer through down-regulation of PTEN expression

Sun

Lei

Hou

et al. 2019

CMAR

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BackgroundPUF60 is a splicing variant of far upstream element binding protein 1-interacting repressor, which is abnormally expressed in a variety of tumors and is closely involved in their progression. However, whether PUF60 participates in the occurrence and development of breast cancer remains unknown. Therefore, the objective of the current study is to explore the effects and mechanism of PUF60 in the progression of breast cancer.MethodsPUF60 expression patterns in breast cancer tissues and cells were determined by RT-PCR and Western blotting. The relationship between PUF60 expression and patients’ clinical features and outcome was evaluated to assess the potential of PUF60 as a marker for progression and prognosis prediction. CCK-8, flow cytometry, transwell and in vivo tumor formation assays were used to detect cell proliferation, apoptosis, migration, invasion and tumorigenesis. The effects of PUF60 on the activation of PTEN/PI3K/AKT were also evaluated by Western blotting and immunofluorescence assays.ResultsThe expression of PUF60 was elevated in breast cancer tissue samples and cell lines, and its high expression was closely associated with the high incidence of lymph node metastasis and advanced TNM stage. Besides, upregulation of PUF60 with lentivirus infection significantly increased the growth, migration, and invasion and repressed the apoptosis of breast cancer HCC1937 and MDA-MB-231 cells, while silencing of PUF60 with shRNA showed the opposite results. Moreover, PUF60 upregulation promoted the expression of p-AKT, PI3K, and mTOR, while decreased PTEN expression through inhibiting its stability and enhancing its ubiquitination. Furthermore, upregulation of PUF60 promoted the tumorigenesis in vivo, whereas this effect was impaired when PTEN expression was upregulated in MDA-MB-231 and HCC1937 cells.ConclusionThis study demonstrates that PUF60 is highly expressed in breast cancer; upregulation of PUF60 accelerates the progression of breast cancer through PTEN inhibition.

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“…The results of a cohort study demonstrated that SF3B1 mutations occur in >20% of patients with uveal melanoma ( 39 ). SFs are also involved in the biological processes of BRCA, such as tumorigenesis, growth, infiltration and metastasis, and are thus involved in prognosis ( 9 , 12 , 40 – 42 ). SFs and AS have been found in the immune-evasion pathway of tumors ( 43 ).…”

Section: Discussionmentioning

confidence: 99%

“…The role of AS in BRCA has recently been investigated, with studies analyzing certain AS events in breast cancer; these studies have demonstrated the potential for specific AS events to classify and diagnose cancer (9,10). Tien et al (11) demonstrated that the mutation of cyclin-dependent kinase 12, which disrupts DNA repair, affected a DNAJB6 isoform and the DNA damage response activator by regulating last-exon splicing; thereby causing tumorigenesis and invasion.…”

Section: Introductionmentioning

confidence: 99%

Wide‑ranging analysis of survival‑related alternative splicing events in invasive breast carcinoma

Jia

Huang

et al. 2020

Oncol Lett

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Invasive breast carcinoma (BRCA) is a serious disease that threatens the survival time of those affected. Alternative splicing (AS) involved in BRCA pathogenesis may be a potential therapeutic target. However, to the best of our knowledge, a systematic analysis of survival-related alternative splicing events (SREs) has not yet been reported. The aim of the present study was to identify SREs and analyze their potential biological functions as BRCA prognostic biomarkers. An UpSet plot demonstrated AS global characteristics. Cox's proportional hazards regression model quantitatively demonstrated the prognostic relevance of AS events. Functional enrichment analysis investigated the potential pathways through which AS events affect BRCA progression. The receiver operating characteristic curve model determined the clinical significance of AS events represented using percent-spliced-in (PSI) values. The regulatory network of splicing factors (SFs) and AS events laid the foundation for studying the role of SFs in BRCA. The present study identified 1,215 SREs and their distribution characteristics, suggesting that AS events in exon skipping (ES) primarily exerted normal physiological functions, while AS events in alternative terminator sites had the most significant prognostic effect. The present study demonstrated that survival-associated genes are involved primarily in certain biological processes of ribosomal proteins. In the diagnostic model, the alternative acceptor site, alternative donor site, alternative promoter site and ES performed well. ELAVL4 was the key gene associated with prognosis and SREs. In conclusion, a number of AS events affect BRCA initiation, progression and prognosis. The PSI value of AS events has the potential to diagnose BRCA and predict a prognosis; however, this must be confirmed in additional studies.

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Splicing dysregulation as a driver of breast cancer

Cited by 32 publications

References 93 publications

Cell-free transcription in Xenopus egg extract

Cell-free transcription in Xenopus egg extract

PUF60 accelerates the progression of breast cancer through down-regulation of PTEN expression

Wide‑ranging analysis of survival‑related alternative splicing events in invasive breast carcinoma

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