Proteogenomic analysis of Inhibitor of Differentiation 4 (ID4) in basal-like breast cancer
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Published:2020-06-11
Issue:1
Volume:22
Page:
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ISSN:1465-542X
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Container-title:Breast Cancer Research
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language:en
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Short-container-title:Breast Cancer Res
Author:
Baker Laura A., Holliday Holly, Roden Daniel, Krisp Christoph, Wu Sunny Z., Junankar Simon, Serandour Aurelien A., Mohammed Hisham, Nair Radhika, Sankaranarayanan Geetha, Law Andrew M. K., McFarland Andrea, Simpson Peter T., Lakhani Sunil, Dodson Eoin, Selinger Christina, Anderson Lyndal, Samimi Goli, Hacker Neville F., Lim Elgene, Ormandy Christopher J., Naylor Matthew J., Simpson Kaylene, Nikolic Iva, O’Toole Sandra, Kaplan Warren, Cowley Mark J., Carroll Jason S., Molloy Mark, Swarbrick AlexanderORCID
Abstract
Abstract
Background
Basal-like breast cancer (BLBC) is a poorly characterised, heterogeneous disease. Patients are diagnosed with aggressive, high-grade tumours and often relapse with chemotherapy resistance. Detailed understanding of the molecular underpinnings of this disease is essential to the development of personalised therapeutic strategies. Inhibitor of differentiation 4 (ID4) is a helix-loop-helix transcriptional regulator required for mammary gland development. ID4 is overexpressed in a subset of BLBC patients, associating with a stem-like poor prognosis phenotype, and is necessary for the growth of cell line models of BLBC through unknown mechanisms.
Methods
Here, we have defined unique molecular insights into the function of ID4 in BLBC and the related disease high-grade serous ovarian cancer (HGSOC), by combining RIME proteomic analysis, ChIP-seq mapping of genomic binding sites and RNA-seq.
Results
These studies reveal novel interactions with DNA damage response proteins, in particular, mediator of DNA damage checkpoint protein 1 (MDC1). Through MDC1, ID4 interacts with other DNA repair proteins (γH2AX and BRCA1) at fragile chromatin sites. ID4 does not affect transcription at these sites, instead binding to chromatin following DNA damage. Analysis of clinical samples demonstrates that ID4 is amplified and overexpressed at a higher frequency in BRCA1-mutant BLBC compared with sporadic BLBC, providing genetic evidence for an interaction between ID4 and DNA damage repair deficiency.
Conclusions
These data link the interactions of ID4 with MDC1 to DNA damage repair in the aetiology of BLBC and HGSOC.
Funder
National Health and Medical Research Council
Publisher
Springer Science and Business Media LLC
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