Proteogenomic analysis of inhibitor of differentiation 4 (ID4) in basal-like breast cancer

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

doi:10.1186/s13058-020-01306-6

Proteogenomic analysis of inhibitor of differentiation 4 (ID4) in basal-like breast cancer

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 LimChristopher J. Ormandy, Matthew J. Naylor, Kaylene Simpson, Iva Nikolic, Sandra O’Toole, Warren Kaplan, Mark J. Cowley, Jason S. Carroll, Mark Molloy, Alexander Swarbrick

Western Sydney University

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	63
Number of pages	18
Journal	Breast Cancer Research
Volume	22
DOIs	https://doi.org/10.1186/s13058-020-01306-6
Publication status	Published - 2020

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© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

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Baker, L. A., Holliday, H., Roden, D., Krisp, C., Wu, S. Z., Junankar, S., Serandour, A. A., Mohammed, H., Nair, R., Sankaranarayanan, G., Law, A. M. K., McFarland, A., Simpson, P. T., Lakhani, S., Dodson, E., Selinger, C., Anderson, L., Samimi, G., Hacker, N. F., ... Swarbrick, A. (2020). Proteogenomic analysis of inhibitor of differentiation 4 (ID4) in basal-like breast cancer. Breast Cancer Research, 22, Article 63. https://doi.org/10.1186/s13058-020-01306-6

@article{ab6a4494bb474a018ba2a290c9fac449,

title = "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.",

author = "Baker, {Laura A.} and Holly Holliday and Daniel Roden and Christoph Krisp and Wu, {Sunny Z.} and Simon Junankar and Serandour, {Aurelien A.} and Hisham Mohammed and Radhika Nair and Geetha Sankaranarayanan and Law, {Andrew M. K.} and Andrea McFarland and Simpson, {Peter T.} and Sunil Lakhani and Eoin Dodson and Christina Selinger and Lyndal Anderson and Goli Samimi and Hacker, {Neville F.} and Elgene Lim and Ormandy, {Christopher J.} and Naylor, {Matthew J.} and Kaylene Simpson and Iva Nikolic and Sandra O{\textquoteright}Toole and Warren Kaplan and Cowley, {Mark J.} and Carroll, {Jason S.} and Mark Molloy and Alexander Swarbrick",

year = "2020",

doi = "10.1186/s13058-020-01306-6",

language = "English",

volume = "22",

journal = "Breast Cancer Research",

issn = "1465-5411",

publisher = "Current Medicine Group ",

}

Baker, LA, Holliday, H, Roden, D, Krisp, C, Wu, SZ, Junankar, S, Serandour, AA, Mohammed, H, Nair, R, Sankaranarayanan, G, Law, AMK, McFarland, A, Simpson, PT, Lakhani, S, Dodson, E, Selinger, C, Anderson, L, Samimi, G, Hacker, NF, Lim, E, Ormandy, CJ, Naylor, MJ, Simpson, K, Nikolic, I, O’Toole, S, Kaplan, W, Cowley, MJ, Carroll, JS, Molloy, M & Swarbrick, A 2020, 'Proteogenomic analysis of inhibitor of differentiation 4 (ID4) in basal-like breast cancer', Breast Cancer Research, vol. 22, 63. https://doi.org/10.1186/s13058-020-01306-6

TY - JOUR

T1 - Proteogenomic analysis of inhibitor of differentiation 4 (ID4) in basal-like breast cancer

AU - Baker, Laura A.

AU - Holliday, Holly

AU - Roden, Daniel

AU - Krisp, Christoph

AU - Wu, Sunny Z.

AU - Junankar, Simon

AU - Serandour, Aurelien A.

AU - Mohammed, Hisham

AU - Nair, Radhika

AU - Sankaranarayanan, Geetha

AU - Law, Andrew M. K.

AU - McFarland, Andrea

AU - Simpson, Peter T.

AU - Lakhani, Sunil

AU - Dodson, Eoin

AU - Selinger, Christina

AU - Anderson, Lyndal

AU - Samimi, Goli

AU - Hacker, Neville F.

AU - Lim, Elgene

AU - Ormandy, Christopher J.

AU - Naylor, Matthew J.

AU - Simpson, Kaylene

AU - Nikolic, Iva

AU - O’Toole, Sandra

AU - Kaplan, Warren

AU - Cowley, Mark J.

AU - Carroll, Jason S.

AU - Molloy, Mark

AU - Swarbrick, Alexander

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

UR - https://hdl.handle.net/1959.7/uws:59351

U2 - 10.1186/s13058-020-01306-6

DO - 10.1186/s13058-020-01306-6

M3 - Article

SN - 1465-5411

VL - 22

JO - Breast Cancer Research

JF - Breast Cancer Research

M1 - 63

ER -

Proteogenomic analysis of inhibitor of differentiation 4 (ID4) in basal-like breast cancer

Abstract

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