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

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.

Mediator of DNA damage checkpoint 1 (MDC1) is a novel estrogen receptor co-regulator in invasive lobular carcinoma of the breast

“…MDC1 is also a tumor suppressor in tumorigenesis models, such as in Mdc1-knockout mice which show increased tumorigenesis due to increased genomic instability [51][52][53][54]. MDC1 also functions as a tumor suppressor in DDR in ER-negative breast cancer, where MDC1 links ID4 to the BRCA1 DDR network [55]. However, our data contrast the tumor suppressor roles of MDC1 in DDR, and instead suggest an oncogenic role in mediating ER function and ERmediated proliferation.…”

Transitional dynamics of cancer stem cells in invasion and metastasis

“…Cytokines and chemokines in tumor microenvironment and epigenetic and transcription factors are other commonly used tools to convert non-stem cancer cells into iCSCs. Inhibitor of differentiation 4 (ID4) was found to dedifferentiate non-stem glioma cells into glioma stem cells [105] and also associated with a stem-like poor prognosis phenotype in triple negative breast cancer [106] . Several reports indicate that dedifferentiation-redifferentiation process is critical for carcinogenesis, selective survival of tumor stem cells that drives invasion and metastases.…”