Proteogenomic Analysis of Inhibitor of Differentiation 4 (ID4) in Basal-like Breast Cancer

Overview

Journal Breast Cancer Res

Specialty Oncology

Date 2020 Jun 13

PMID 32527287

Citations 6

Authors

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 OToole

Warren Kaplan

Mark J Cowley

Jason S Carroll

Mark Molloy

Alexander Swarbrick

Affiliations

Soon will be listed here.

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.

Citing Articles

Image-guided metabolomics and transcriptomics reveal tumour heterogeneity in luminal A and B human breast cancer beyond glucose tracer uptake.

Yang Q, Deng S, Preibsch H, Schade T, Koch A, Berezhnoy G Clin Transl Med. 2024; 14(2):e1550.

PMID: 38332687 PMC: 10853679. DOI: 10.1002/ctm2.1550.

ID4-dependent secretion of VEGFA enhances the invasion capability of breast cancer cells and activates YAP/TAZ via integrin β3-VEGFR2 interaction.

Benedetti A, Turco C, Gallo E, Daralioti T, Sacconi A, Pulito C Cell Death Dis. 2024; 15(2):113.

PMID: 38321003 PMC: 10847507. DOI: 10.1038/s41419-024-06491-2.

Mediator of DNA Damage Checkpoint 1 (MDC1) Is a Novel Estrogen Receptor Coregulator in Invasive Lobular Carcinoma of the Breast.

Sottnik J, Bordeaux E, Mehrotra S, Ferrara S, Goodspeed A, Costello J Mol Cancer Res. 2021; 19(8):1270-1282.

PMID: 33947745 PMC: 8349796. DOI: 10.1158/1541-7786.MCR-21-0025.

Id4 Suppresses the Growth and Invasion of Colorectal Cancer HCT116 Cells through CK18-Related Inhibition of AKT and EMT Signaling.

Chen H, Yu Y, Sun Y, Huang C, Li J, Liu F J Oncol. 2021; 2021:6660486.

PMID: 33936204 PMC: 8060092. DOI: 10.1155/2021/6660486.

ID1 and ID4 Are Biomarkers of Tumor Aggressiveness and Poor Outcome in Immunophenotypes of Breast Cancer.

Garcia-Escolano M, Montoyo-Pujol Y, Ortiz-Martinez F, Ponce J, Delgado-Garcia S, Martin T Cancers (Basel). 2021; 13(3).

PMID: 33514024 PMC: 7865969. DOI: 10.3390/cancers13030492.

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