| Autor: |
Laura A. Baker, Holly Holliday, Daniel Roden, Christoph Krisp, Sunny Z. Wu, Simon Junankar, Aurelien A. Serandour, Hisham Mohammed, Radhika Nair, Geetha Sankaranarayanan, Andrew M. K. Law, Andrea McFarland, Peter T. Simpson, Sunil Lakhani, Eoin Dodson, Christina Selinger, Lyndal Anderson, Goli Samimi, Neville F. Hacker, Elgene Lim, Christopher J. Ormandy, Matthew J. Naylor, Kaylene Simpson, Iva Nikolic, Sandra O’Toole, Warren Kaplan, Mark J. Cowley, Jason S. Carroll, Mark Molloy, Alexander Swarbrick |
| Jazyk: |
angličtina |
| Rok vydání: |
2020 |
| Předmět: |
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| Zdroj: |
Breast Cancer Research, Vol 22, Iss 1, Pp 1-18 (2020) |
| Druh dokumentu: |
article |
| ISSN: |
1465-542X |
| DOI: |
10.1186/s13058-020-01306-6 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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