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

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 KaplanChristopher Ormandy, Ewan K A Millar, Sandra O'Toole, Kyuson Yun, Alexander Swarbrick

Research Institute

Research output: Contribution to journal › Article

35 Scopus citations

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.

Original language	English (US)
Pages (from-to)	6548
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms7548
State	Published - Mar 27 2015

Keywords

Animals
Breast Neoplasms
Cell Line, Tumor
Female
Gene Knock-In Techniques
Humans
Inhibitor of Differentiation Proteins
Mammary Glands, Animal
Mice
Neoplasm Transplantation
Phenotype
RNA, Messenger
Real-Time Polymerase Chain Reaction
Stem Cells
Journal Article
Research Support, Non-U.S. Gov't

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Junankar, S., Baker, L. A., Roden, D. L., Nair, R., Elsworth, B., Gallego-Ortega, D., Lacaze, P., Cazet, A., Nikolic, I., Teo, W. S., Yang, J., McFarland, A., Harvey, K., Naylor, M. J., Lakhani, S. R., Simpson, P. T., Raghavendra, A., Saunus, J., Madore, J., ... Swarbrick, A. (2015). ID4 controls mammary stem cells and marks breast cancers with a stem cell-like phenotype. Nature Communications, 6, 6548. https://doi.org/10.1038/ncomms7548

ID4 controls mammary stem cells and marks breast cancers with a stem cell-like phenotype. / Junankar, Simon; Baker, Laura A; Roden, Daniel L; Nair, Radhika; Elsworth, Ben; Gallego-Ortega, David; Lacaze, Paul; Cazet, Aurélie; Nikolic, Iva; Teo, Wee Siang; Yang, Jessica; McFarland, Andrea; Harvey, Kate; Naylor, Matthew J; Lakhani, Sunil R; Simpson, Peter T; Raghavendra, Ashwini; Saunus, Jodi; Madore, Jason; Kaplan, Warren; Ormandy, Christopher; Millar, Ewan K A; O'Toole, Sandra; Yun, Kyuson; Swarbrick, Alexander.

In: Nature Communications, Vol. 6, 27.03.2015, p. 6548.

Research output: Contribution to journal › Article

Junankar, S, Baker, LA, Roden, DL, Nair, R, Elsworth, B, Gallego-Ortega, D, Lacaze, P, Cazet, A, Nikolic, I, Teo, WS, Yang, J, McFarland, A, Harvey, K, Naylor, MJ, Lakhani, SR, Simpson, PT, Raghavendra, A, Saunus, J, Madore, J, Kaplan, W, Ormandy, C, Millar, EKA, O'Toole, S, Yun, K & Swarbrick, A 2015, 'ID4 controls mammary stem cells and marks breast cancers with a stem cell-like phenotype', Nature Communications, vol. 6, pp. 6548. https://doi.org/10.1038/ncomms7548

Junankar, Simon ; Baker, Laura A ; Roden, Daniel L ; Nair, Radhika ; Elsworth, Ben ; Gallego-Ortega, David ; Lacaze, Paul ; Cazet, Aurélie ; Nikolic, Iva ; Teo, Wee Siang ; Yang, Jessica ; McFarland, Andrea ; Harvey, Kate ; Naylor, Matthew J ; Lakhani, Sunil R ; Simpson, Peter T ; Raghavendra, Ashwini ; Saunus, Jodi ; Madore, Jason ; Kaplan, Warren ; Ormandy, Christopher ; Millar, Ewan K A ; O'Toole, Sandra ; Yun, Kyuson ; Swarbrick, Alexander. / ID4 controls mammary stem cells and marks breast cancers with a stem cell-like phenotype. In: Nature Communications. 2015 ; Vol. 6. pp. 6548.

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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.",

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AU - McFarland, Andrea

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AU - Naylor, Matthew J

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AU - Raghavendra, Ashwini

AU - Saunus, Jodi

AU - Madore, Jason

AU - Kaplan, Warren

AU - Ormandy, Christopher

AU - Millar, Ewan K A

AU - O'Toole, Sandra

AU - Yun, Kyuson

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AB - 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.

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