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 output: Contribution to journal › Article › peer-review

48 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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10.1038/ncomms7548

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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

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

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title = "ID4 controls mammary stem cells and marks breast cancers with a stem cell-like phenotype",

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 - Baker, Laura A

AU - Roden, Daniel L

AU - Nair, Radhika

AU - Elsworth, Ben

AU - Gallego-Ortega, David

AU - Lacaze, Paul

AU - Cazet, Aurélie

AU - Nikolic, Iva

AU - Teo, Wee Siang

AU - Yang, Jessica

AU - McFarland, Andrea

AU - Harvey, Kate

AU - Naylor, Matthew J

AU - Lakhani, Sunil R

AU - Simpson, Peter T

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

AU - Swarbrick, Alexander

PY - 2015/3/27

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N2 - 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.

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.

KW - Animals

KW - Breast Neoplasms

KW - Cell Line, Tumor

KW - Female

KW - Gene Knock-In Techniques

KW - Humans

KW - Inhibitor of Differentiation Proteins

KW - Mammary Glands, Animal

KW - Mice

KW - Neoplasm Transplantation

KW - Phenotype

KW - RNA, Messenger

KW - Real-Time Polymerase Chain Reaction

KW - Stem Cells

KW - Journal Article

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

U2 - 10.1038/ncomms7548

DO - 10.1038/ncomms7548

M3 - Article

C2 - 25813983

SN - 2041-1723

VL - 6

SP - 6548

JO - Nature Communications

JF - Nature Communications

ER -

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

Abstract

Keywords

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