New insights into the role of NF1 in cancer

Sabová, L; Kretova, Miroslava; Luciaková, Katarína

doi:10.4149/neo_2013_031

Cited by 8 publications

(8 citation statements)

References 63 publications

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“…Ras/MAPK activity can be aberrantly stimulated via the overexpression of RTKs or copy number alterations of KRAS and BRAF . Also, loss of DUSP4 or somatic alterations of NF1 in TNBC can contribute to the activation of RAF/MEK/ERK pathway [ 74 , 75 ]. Preclinical studies have demonstrated that basal type breast cancer cells have an activated RAS-like transcriptional program and are significantly more sensitive to MEK inhibitors compared with luminal and HER-2 amplified lines.…”

Section: Main Textmentioning

confidence: 99%

Therapeutic landscape in mutational triple negative breast cancer

Shi

Jin

et al. 2018

Mol Cancer

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Triple negative breast cancer (TNBC) is a heterogeneous disease with aggressive behavior and poor prognosis. Genomic sequencing has detected a distinctive mutational portrait of both the germline and somatic alterations in TNBC, which is staggeringly different from other breast cancer subtypes. The clinical utility of sequencing germline BRCA1/2 genes has been well established in TNBC. However, for other predisposition genes, studies concerning the risk and penetrance to TNBC are relatively scarce. Very few recurrent mutations, including TP53 and PI3KCA mutations, together with a long tail of individually rare mutations occur in TNBC. These combined effects of genomic alterations drive TNBC progression. Given the complexity and heterogeneity of TNBC, clinical interpretation of the genomic alterations in TNBC may pave a new way for the treatment of TNBC. In this review, we summarized the germline and somatic mutation profiles of TNBC and discussed the current and upcoming therapeutic strategies targeting the mutant proteins or pathways to enable tailored-therapeutics.

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Section: Main Textmentioning

confidence: 99%

Therapeutic landscape in mutational triple negative breast cancer

Shi

Jin

et al. 2018

Mol Cancer

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“…In contrast to the highly conserved N-terminal DNA binding domain, the C-terminal region of NFIB, which encodes a transactivation domain, diverges extensively between other NFI members as well as between isoforms, and therefore might promote interactions with different nuclear regulatory proteins depending on the cellular context ( Gronostajski, 2000 ). Adding to this complexity, post-translational modifications (phosphorylation, O- or N-glycosylation) can significantly influence the activity of NFI proteins ( Sabova et al, 2013 ). Fig.…”

Section: Nfib Gene Regulation and Downstream Targetsmentioning

confidence: 99%

Nuclear Factor I/B: A Master Regulator of Cell Differentiation with Paradoxical Roles in Cancer

et al. 2017

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Emerging evidence indicates that nuclear factor I/B (NFIB), a transcription factor required for proper development and regulation of cellular differentiation in several tissues, also plays critical roles in cancer. Despite being a metastatic driver in small cell lung cancer and melanoma, it has become apparent that NFIB also exhibits tumour suppressive functions in many malignancies. The contradictory contributions of NFIB to both the inhibition and promotion of tumour development and progression, corroborates its diverse and context-dependent roles in many tissues and cell types. Considering the frequent involvement of NFIB in cancer, a better understanding of its multifaceted nature may ultimately benefit the development of novel strategies for the management of a broad spectrum of malignancies. Here we discuss recent findings which bring to light NFIB as a crucial and paradoxical player in cancer.

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“…The protein product of NF1 gene, neurofibromin, is a multifunctional protein involved in many cellular signaling pathways, including RAS/MAPK and mTOR pathways, both of which are dysregulated in many cancer types. 21 CTNNB1, Wnt/b-catenin, is a highly complex pathway and plays a vital role in bone development and homeostasis and is dysregulated in many human malignancies, including bone cancers and, especially, osteosarcomas. 22 Although on a small sample set, we were able to identify a preliminary set of 9 probes (8 gene loci: FAM181B, KANK2, NPR3, PON3, RAB32, RAI1, SLC16A5, and ZNF397OS) that were differentially methylated between control samples and chordomas that recurred and tumors that did not recur.…”

Section: -14mentioning

confidence: 99%

Genome-wide DNA methylation profiling of recurrent and non-recurrent chordomas

et al. 2015

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Chordomas are an aggressive rare type of malignant bone tumors arising from the remnant of the notochord. Chordomas occur mainly in vertebral bones and account for 1-4% of malignant bone tumors. Management and treatment of chordomas are difficult as they are resistant to conventional chemotherapy; therefore, they are mainly treated with surgery and radiation therapy. In this study, we performed DNA methylation profiling of 26 chordomas and normal nucleus pulposus samples plus UCH-1 chordoma cell line using the Illumina Infinium HumanMethylation450 BeadChips. Combined bisulfite restriction analysis and bisulfite sequencing was used to confirm the methylation data. Gene expression was analyzed using RT-PCR before and after 5-aza-2'-deoxycytidine (5-azaDC) treatment of chordoma cell lines. Analysis of the HumanMethylation450 BeadChip data led to the identification of 8,819 loci (2.9%) that were significantly differentially methylated (>0.2 average b-value difference) between chordomas and nucleus pulposus samples (adjusted P < 0.05). Among these, 5,868 probes (66.5%) were hypomethylated, compared to 2,951 (33.5%) loci that were hypermethylated in chordomas compared to controls. From the 2,951 differentially hypermethylated probes, 33.3% were localized in the promoter region (982 probes) and, among these, 104 probes showed cancer-specific hypermethylation. Ingenuity Pathway Analysis indicates that the cancer-specific differentially methylated loci are involved in various networks including cancer disease, nervous system development and function, cell death and survival, cellular growth, cellular development, and proliferation. Furthermore, we identified a subset of probes that were differentially methylated between recurrent and non-recurrent chordomas. BeadChip methylation data was confirmed for these genes and gene expression was shown to be upregulated in methylated chordoma cell lines after treatment with 5-azaDC. Understanding epigenetic changes in chordomas may provide insights into chordoma tumorigenesis and development of epigenetic biomarkers.

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New insights into the role of NF1 in cancer

Cited by 8 publications

References 63 publications

Therapeutic landscape in mutational triple negative breast cancer

Therapeutic landscape in mutational triple negative breast cancer

Nuclear Factor I/B: A Master Regulator of Cell Differentiation with Paradoxical Roles in Cancer

Genome-wide DNA methylation profiling of recurrent and non-recurrent chordomas

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