ID4 controls mammary stem cells and marks breast cancers with a stem cell-like phenotype

Simon Junankar; Laura A Baker; Daniel L Roden; Radhika Nair; Ben Elsworth; David Gallego-Ortega; Paul Lacaze; Aurélie Cazet; Iva Nikolic; Wee Siang Teo; Jessica Yang; Andrea McFarland; Kate Harvey; Matthew J Naylor; Sunil R Lakhani; Peter T Simpson; Ashwini Raghavendra; Jodi Saunus; Jason Madore; Warren Kaplan; Christopher Ormandy; Ewan K A Millar; Sandra O'Toole; Kyuson Yun; Alexander Swarbrick

doi:10.1038/ncomms7548

ID4 controls mammary stem cells and marks breast cancers with a stem cell-like phenotype

Nat Commun. 2015 Mar 27:6:6548. doi: 10.1038/ncomms7548.

Authors

Simon Junankar¹, Laura A Baker¹, Daniel L Roden¹, Radhika Nair¹, Ben Elsworth¹, David Gallego-Ortega¹, Paul Lacaze², Aurélie Cazet¹, Iva Nikolic¹, Wee Siang Teo³, Jessica Yang³, Andrea McFarland³, Kate Harvey³, Matthew J Naylor⁴, Sunil R Lakhani⁵, Peter T Simpson⁶, Ashwini Raghavendra⁷, Jodi Saunus⁷, Jason Madore⁷, Warren Kaplan³, Christopher Ormandy¹, Ewan K A Millar⁸, Sandra O'Toole⁹, Kyuson Yun¹⁰, Alexander Swarbrick¹

Affiliations

¹ 1] The Kinghorn Cancer Centre &Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia [2] St Vincent's Clinical School, Faculty of Medicine, UNSW, Kensington, New South Wales 2033, Australia.
² Millennium Science Pty Ltd, 4 Miles Street, Mulgrave, Victoria 3170, Australia.
³ The Kinghorn Cancer Centre &Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.
⁴ 1] The Kinghorn Cancer Centre &Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia [2] St Vincent's Clinical School, Faculty of Medicine, UNSW, Kensington, New South Wales 2033, Australia [3] Discipline of Physiology and Bosch Institute, School of Medical Sciences, University of Sydney, Camperdown, New South Wales 2006, Australia.
⁵ 1] UQ Centre for Clinical Research, The University of Queensland, Brisbane, Queensland 4072, Australia [2] School of Medicine, The University of Queensland, Brisbane, Queensland 4072, Australia [3] Pathology Queensland, The Royal Brisbane and Women's Hospital, Herston, Queensland 4029, Australia [4] QIMR Berghofer Medical Research Institute, Herston, Queensland 4029, Australia.
⁶ 1] UQ Centre for Clinical Research, The University of Queensland, Brisbane, Queensland 4072, Australia [2] School of Medicine, The University of Queensland, Brisbane, Queensland 4072, Australia [3] QIMR Berghofer Medical Research Institute, Herston, Queensland 4029, Australia.
⁷ 1] UQ Centre for Clinical Research, The University of Queensland, Brisbane, Queensland 4072, Australia [2] QIMR Berghofer Medical Research Institute, Herston, Queensland 4029, Australia.
⁸ 1] The Kinghorn Cancer Centre &Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia [2] Department of Anatomical Pathology, South Eastern Area Laboratory Service, St George Hospital, Kogarah, New South Wales 2217, Australia [3] School of Medical Sciences, UNSW, Kensington, New South Wales 2033, Australia [4] Faculty of Medicine &Health Sciences, University of Western Sydney, Campbelltown, New South Wales 2560, Australia.
⁹ 1] The Kinghorn Cancer Centre &Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia [2] Department of Anatomical Pathology, Sydpath, St Vincent's Hospital, Darlinghurst, New South Wales 2010, Australia [3] Sydney Medical School, University of Sydney, Camperdown, New South Wales 2006, Australia.
¹⁰ The Jackson Laboratory, Bar Harbor, Maine 04609, USA.

PMID: 25813983
DOI: 10.1038/ncomms7548

Abstract

Basal-like breast cancer (BLBC) is a heterogeneous disease with poor prognosis; however, its cellular origins and aetiology are poorly understood. In this study, we show that inhibitor of differentiation 4 (ID4) is a key regulator of mammary stem cell self-renewal and marks a subset of BLBC with a putative mammary basal cell of origin. Using an ID4GFP knock-in reporter mouse and single-cell transcriptomics, we show that ID4 marks a stem cell-enriched subset of the mammary basal cell population. ID4 maintains the mammary stem cell pool by suppressing key factors required for luminal differentiation. Furthermore, ID4 is specifically expressed by a subset of human BLBC that possess a very poor prognosis and a transcriptional signature similar to a mammary stem cell. These studies identify ID4 as a mammary stem cell regulator, deconvolute the heterogeneity of BLBC and link a subset of mammary stem cells to the aetiology of BLBC.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Breast Neoplasms / genetics*
Breast Neoplasms / metabolism
Cell Line, Tumor
Female
Gene Knock-In Techniques
Humans
Inhibitor of Differentiation Proteins / genetics*
Inhibitor of Differentiation Proteins / metabolism
Mammary Glands, Animal / cytology*
Mammary Glands, Animal / metabolism
Mice
Neoplasm Transplantation
Phenotype
RNA, Messenger / metabolism*
Real-Time Polymerase Chain Reaction
Stem Cells / metabolism*

Substances

ID4 protein, human
Idb4 protein, mouse
Inhibitor of Differentiation Proteins
RNA, Messenger