Proteogenomic analysis of Inhibitor of Differentiation 4 (ID4) in basal-like breast cancer

• Published in: Breast cancer research : BCR Vol. 22; no. 1; p. 63
• Main Authors: 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, Alexander
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 11-06-2020; BioMed Central; BMC
• Subjects: Analysis; Animals; Antibodies; Apoptosis - physiology; Binding sites; BRCA1 protein; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Carcinoma, Basal Cell - genetics; Carcinoma, Basal Cell - metabolism; Carcinoma, Basal Cell - pathology; Cell culture; Cell Differentiation - physiology; Cell Line, Tumor; Cell Proliferation - physiology; Chemoresistance; Chemotherapy; Chromatin; Chromatin - genetics; Chromatin - metabolism; Deoxyribonucleic acid; DNA; DNA Damage; DNA repair; Female; Gene expression; Gene mapping; Health aspects; Helix-loop-helix; Helix-loop-helix proteins; Heterografts; Humans; Inhibitor of Differentiation Proteins - genetics; Inhibitor of Differentiation Proteins - metabolism; Mammary gland; Mass spectrometry; Medical prognosis; Mice; Mice, Inbred NOD; Mice, SCID; Mutation; Ovarian cancer; Phenotypes; Phosphatase; Prognosis; Proteins; Proteogenomics; Proteomics; Ribonucleic acid; RNA; Scientific equipment industry; Scientific imaging; Transcription; Transcription (Genetics); Transcription factor; Tumor Cells, Cultured; Tumors; Australia; United States; United States > US; Germany; Helix-loop-helix; Breast cancer; Transcription factor; DNA damage
• ISSN: 1465-542X; 1465-5411; 1465-542X
• DOI: 10.1186/s13058-020-01306-6

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.
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.
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.
These data link the interactions of ID4 with MDC1 to DNA damage repair in the aetiology of BLBC and HGSOC.