Genome-wide DNA methylation assessment of ‘BRCA1-like’ early-onset breast cancer: Data from the Australian Breast Cancer Family Registry

Scott, Cameron M.; Wong, Ee Ming; Joo, Ji Hoon Eric; Dugué, Pierre Antoine; Jung, Chol Hee; O’Callaghan, Neil; Dowty, James G.; Giles, Graham G.; Hopper, John L.; Southey, Melissa C.

doi:10.1016/j.yexmp.2018.11.006

Cited by 17 publications

(21 citation statements)

References 42 publications

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“…Notably, eight of the germline BRCA1 wildtype tumors had high cyclin E1. We hypothesized that these may be BRCA1 methylated since our cohort was selected for familial breast cancers where BRCA1 methylation is not infrequent (34). Consequently, we examined the relationship between BRCA1 methylation and cyclin E1 protein expression by interrogating the breast cancer dataset of the TCGA.…”

Section: Resultsmentioning

confidence: 99%

Cyclin E1 protein is stabilized inBRCA1mutated breast cancers leading to synergy between CDK2 and PARP inhibitors

Aziz

Portman

et al. 2020

Preprint

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26Basal-like breast cancers (BLBC) are aggressive breast cancers that respond poorly 27 to targeted therapies and chemotherapies. In order to define therapeutically 28 targetable subsets of BLBC we examined two markers: cyclin E1 and BRCA1 loss. 29 In high grade serous ovarian cancer (HGSOC) these markers are mutually exclusive, 30 and define therapeutic subsets. We tested the same hypothesis for BLBC. 31Using a BLBC cohort enriched for BRCA1 loss, we identified convergence between 32 BRCA1 loss and high cyclin E1 expression, in contrast to HGSOC in which CCNE1 33 amplification drives increased cyclin E1 gene expression. Instead, BRCA1 loss 34 stabilized cyclin E1 during the cell cycle. Using siRNA we showed that BRCA1 loss 35 leads to stabilization of cyclin E1 by reducing phospho-cyclin E1-T62, and 36 conversely the overexpression of BRCA1 increased phospho-T62. Mutation of cyclin 37 E1-T62 to alanine increased cyclin E1 stability. We showed that tumors with high 38 cyclin E1/BRCA1 mutation in the BLBC cohort had decreased phospho-T62, 39 supporting this hypothesis. 40Since cyclin E1/CDK2 protects cells from DNA damage and cyclin E1 is elevated in 41 BRCA1 mutant cancers, we hypothesized that CDK2 inhibition would sensitize these 42 cancers to PARP inhibition. CDK2 inhibition induced DNA damage and synergized 43 with PARP inhibitors to reduce cell viability in BRCA1 mutated cell lines. Treatment 44 of BLBC patient-derived xenograft models with combination PARP and CDK2 45 inhibition led to tumor regression and increased survival. We conclude that BRCA1 46 status and high cyclin E1 have potential as predictive biomarkers to dictate the 47 therapeutic use of combination CDK inhibitors/PARP inhibitors in BLBC. 48 3 instability in cancer cells, and is frequently elevated in BLBC (9). Perplexingly, in 65 high grade serous ovarian cancer (HGSOC) cyclin E1 amplification and BRCA1/2 66 mutation are mutually exclusive, presumably because both aberrations drive 67 genomic instability and together they precipitate lethal genomic damage (10-12). 68We recently described two subsets of HGSOC, one where cyclin E1 gene 69 amplification and BRCA1 mutation were mutually exclusive, and another where high 70 cyclin E1 protein expression was due to post-transcriptional deregulation rather than 71 4 gene amplification, and was often concurrent with BRCA1/2 mutation (12). Cyclin E1 72 protein stability is regulated by a multi-step process of specific phosphorylation and 73 ubiquitination, leading to its cyclic expression and turnover (13). Key regulators in the 74 turnover of cyclin E1, such as the ubiquitin ligase component FBXW7 and the 75 deubiquitinase USP28, are frequently dysregulated in cancer (13-15) leading to 76 altered stability of the cyclin E1 protein. 77In this study, we examined whether BRCA1 loss and cyclin E1 gain occurred 78 concurrently or independently in breast cancer. We also explored the mechanisms 79 underpinning high cyclin E1 expression in BRCA1 mutated breast cancer including 80 gene amplification and p...

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Section: Resultsmentioning

confidence: 99%

Cyclin E1 protein is stabilized inBRCA1mutated breast cancers leading to synergy between CDK2 and PARP inhibitors

Aziz

Portman

et al. 2020

Preprint

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“…A growing body of evidence shows that IGF2BP3 has shown its promising value on cancer therapy ( Lochhead et al, 2012 ; Hsu et al, 2015 ). Numerous cancers have been identified the overexpression of IGF2BP3 including lung cancer ( Findeis-Hosey and Xu, 2012 ), breast cancer ( Scott et al, 2018 ), colorectal cancer ( Wei et al, 2017 ; Xu et al, 2019 ), hepatocellular carcinoma ( Shaalan et al, 2018 ), pancreatic cancer ( Chen et al, 2019 ), glioblastoma and ovarian clear cell carcinoma ( Bi et al, 2016 ; Dutoit et al, 2018 ). IGF2BP3 is a carcinoembryonic protein that is highly expressed during embryogenesis, lowly expressed in adult tissues, and re-expressed in malignant tissues ( Palanichamy et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

IGF2BP3 May Contributes to Lung Tumorigenesis by Regulating the Alternative Splicing of PKM

Huang

Zhang

Jiang

et al. 2020

Front. Bioeng. Biotechnol.

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RNA binding proteins (RBPs) play a key role in genome regulation. Here we report the post-transcript regulation of IGF2BP3, which belongs to the insulin-like growth factor 2 mRNA binding protein family. We used iRIP-seq and RNA-seq to analyze the transcript regulation and alternative splicing on IGF2BP3 treated with overexpression cells and control. Overexpressed IGF2BP3 has broadly increased genes expression which involved in G-protein coupled receptor signaling pathway, positive regulation of cell proliferation, and signal transduction. IGF2BP3 regulated alternative splicing of multiple genes mainly clustered at response to hypoxia, negative regulation of transcription, and embryonic development. This study first provides alternative splicing analysis on transcription level of IGF2BP3 regulation, which laid the foundation for later research on IGF2BP3 critical functions.

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“…Studies included breast cancer patients between 48 and 64 years of mean age ( n = 12 studies), and one study included exclusively patients under 40 years old [ 28 ]. Proportion of postmenopausal patients varied from 31 to 100% ( n = 7 studies), with only one study including at least 80% of postmenopausal patients [ 26 ].…”

Section: Resultsmentioning

confidence: 99%

Epigenome-wide DNA methylation and risk of breast cancer: a systematic review

et al. 2020

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Background DNA methylation is a potential biomarker for early detection of breast cancer. However, robust evidence of a prospective relationship between DNA methylation patterns and breast cancer risk is still lacking. The objective of this study is to provide a systematic analysis of the findings of epigenome-wide DNA methylation studies on breast cancer risk, in light of their methodological strengths and weaknesses. Methods We searched major databases (MEDLINE, EMBASE, Web of Science, CENTRAL) from inception up to 30th June 2019, for observational or intervention studies investigating the association between epigenome-wide DNA methylation (using the HM450k or EPIC BeadChip), measured in any type of human sample, and breast cancer risk. A pre-established protocol was drawn up following the Cochrane Reviews rigorous methodology. Study selection, data abstraction, and risk of bias assessment were performed by at least two investigators. A qualitative synthesis and systematic comparison of the strengths and weaknesses of studies was performed. Results Overall, 20 studies using the HM450k BeadChip were included, 17 of which had measured blood-derived DNA methylation. There was a consistent trend toward an association of global blood-derived DNA hypomethylation and higher epigenetic age with higher risk of breast cancer. The strength of associations was modest for global hypomethylation and relatively weak for most of epigenetic age algorithms. Differences in length of follow-up periods may have influenced the ability to detect associations, as studies reporting follow-up periods shorter than 10 years were more likely to observe an association with global DNA methylation. Probe-wise differential methylation analyses identified between one and 806 differentially methylated CpGs positions in 10 studies. None of the identified differentially methylated sites overlapped between studies. Three studies used breast tissue DNA and suffered major methodological issues that precludes any conclusion. Overall risk of bias was critical mainly because of incomplete control of confounding. Important issues relative to data preprocessing could have limited the consistency of results. Conclusions Global DNA methylation may be a short-term predictor of breast cancer risk. Further studies with rigorous methodology are needed to determine spatial distribution of DNA hypomethylation and identify differentially methylated sites associated with risk of breast cancer. Prospero registration number CRD42020147244

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Genome-wide DNA methylation assessment of ‘BRCA1-like’ early-onset breast cancer: Data from the Australian Breast Cancer Family Registry

Cited by 17 publications

References 42 publications

Cyclin E1 protein is stabilized inBRCA1mutated breast cancers leading to synergy between CDK2 and PARP inhibitors

Cyclin E1 protein is stabilized inBRCA1mutated breast cancers leading to synergy between CDK2 and PARP inhibitors

IGF2BP3 May Contributes to Lung Tumorigenesis by Regulating the Alternative Splicing of PKM

Epigenome-wide DNA methylation and risk of breast cancer: a systematic review

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