Frontiers in Cell and Developmental Biology (Jul 2020)
Id Proteins Promote a Cancer Stem Cell Phenotype in Mouse Models of Triple Negative Breast Cancer via Negative Regulation of Robo1
- Wee S. Teo,
- Wee S. Teo,
- Holly Holliday,
- Holly Holliday,
- Nitheesh Karthikeyan,
- Aurélie S. Cazet,
- Aurélie S. Cazet,
- Daniel L. Roden,
- Daniel L. Roden,
- Kate Harvey,
- Christina Valbirk Konrad,
- Reshma Murali,
- Binitha Anu Varghese,
- Archana P. Thankamony,
- Archana P. Thankamony,
- Chia-Ling Chan,
- Chia-Ling Chan,
- Andrea McFarland,
- Simon Junankar,
- Simon Junankar,
- Sunny Ye,
- Jessica Yang,
- Iva Nikolic,
- Iva Nikolic,
- Jaynish S. Shah,
- Laura A. Baker,
- Laura A. Baker,
- Ewan K. A. Millar,
- Ewan K. A. Millar,
- Ewan K. A. Millar,
- Ewan K. A. Millar,
- Matthew J. Naylor,
- Matthew J. Naylor,
- Matthew J. Naylor,
- Christopher J. Ormandy,
- Christopher J. Ormandy,
- Sunil R. Lakhani,
- Warren Kaplan,
- Warren Kaplan,
- Albert S. Mellick,
- Albert S. Mellick,
- Sandra A. O'Toole,
- Sandra A. O'Toole,
- Alexander Swarbrick,
- Alexander Swarbrick,
- Radhika Nair,
- Radhika Nair,
- Radhika Nair
Affiliations
- Wee S. Teo
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Wee S. Teo
- Faculty of Medicine, St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia
- Holly Holliday
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Holly Holliday
- Faculty of Medicine, St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia
- Nitheesh Karthikeyan
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
- Aurélie S. Cazet
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Aurélie S. Cazet
- Faculty of Medicine, St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia
- Daniel L. Roden
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Daniel L. Roden
- Faculty of Medicine, St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia
- Kate Harvey
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Christina Valbirk Konrad
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Reshma Murali
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
- Binitha Anu Varghese
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
- Archana P. Thankamony
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
- Archana P. Thankamony
- Manipal Academy of Higher Education, Manipal, India
- Chia-Ling Chan
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Chia-Ling Chan
- Faculty of Medicine, St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia
- Andrea McFarland
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Simon Junankar
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Simon Junankar
- Faculty of Medicine, St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia
- Sunny Ye
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Jessica Yang
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Iva Nikolic
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Iva Nikolic
- Faculty of Medicine, St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia
- Jaynish S. Shah
- Gene & Stem Cell Therapy Program, Centenary Institute, The University of Sydney, Camperdown, NSW, Australia
- Laura A. Baker
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Laura A. Baker
- Faculty of Medicine, St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia
- Ewan K. A. Millar
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Ewan K. A. Millar
- Department of Anatomical Pathology, NSW Health Pathology, St George Hospital, Kogarah, NSW, Australia
- Ewan K. A. Millar
- School of Medical Sciences, UNSW Sydney, Kensington, NSW, Australia
- Ewan K. A. Millar
- School of Medicine, Western Sydney University, Penrith, NSW, Australia
- Matthew J. Naylor
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Matthew J. Naylor
- Faculty of Medicine, St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia
- Matthew J. Naylor
- School of Medical Sciences, Discipline of Physiology & Bosch Institute, University of Sydney, Sydney, NSW, Australia
- Christopher J. Ormandy
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Christopher J. Ormandy
- Faculty of Medicine, St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia
- Sunil R. Lakhani
- 0UQ Centre for Clinical Research, School of Medicine and Pathology Queensland, Royal Brisbane & Women's Hospital, The University of Queensland, Herston, QLD, Australia
- Warren Kaplan
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Warren Kaplan
- 1Peter Wills Bioinformatics Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Albert S. Mellick
- 2UNSW Medicine, University of NSW, Kensington, NSW, Australia
- Albert S. Mellick
- 3Medical Oncology Group, Ingham Institute for Applied Medical Research, South Western Sydney Clinical School UNSW & CONCERT Translational Cancer Research Centre, Liverpool, NSW, Australia
- Sandra A. O'Toole
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Sandra A. O'Toole
- 4Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia
- Alexander Swarbrick
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Alexander Swarbrick
- Faculty of Medicine, St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia
- Radhika Nair
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Radhika Nair
- Faculty of Medicine, St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia
- Radhika Nair
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
- DOI
- https://doi.org/10.3389/fcell.2020.00552
- Journal volume & issue
-
Vol. 8
Abstract
Breast cancers display phenotypic and functional heterogeneity and several lines of evidence support the existence of cancer stem cells (CSCs) in certain breast cancers, a minor population of cells capable of tumor initiation and metastatic dissemination. Identifying factors that regulate the CSC phenotype is therefore important for developing strategies to treat metastatic disease. The Inhibitor of Differentiation Protein 1 (Id1) and its closely related family member Inhibitor of Differentiation 3 (Id3) (collectively termed Id) are expressed by a diversity of stem cells and are required for metastatic dissemination in experimental models of breast cancer. In this study, we show that ID1 is expressed in rare neoplastic cells within ER-negative breast cancers. To address the function of Id1 expressing cells within tumors, we developed independent murine models of Triple Negative Breast Cancer (TNBC) in which a genetic reporter permitted the prospective isolation of Id1+ cells. Id1+ cells are enriched for self-renewal in tumorsphere assays in vitro and for tumor initiation in vivo. Conversely, depletion of Id1 and Id3 in the 4T1 murine model of TNBC demonstrates that Id1/3 are required for cell proliferation and self-renewal in vitro, as well as primary tumor growth and metastatic colonization of the lung in vivo. Using combined bioinformatic analysis, we have defined a novel mechanism of Id protein function via negative regulation of the Roundabout Axon Guidance Receptor Homolog 1 (Robo1) leading to activation of a Myc transcriptional programme.
Keywords
