AUTHOR=Teo Wee S. , Holliday Holly , Karthikeyan Nitheesh , Cazet Aurélie S. , Roden Daniel L. , Harvey Kate , Konrad Christina Valbirk , Murali Reshma , Varghese Binitha Anu , Thankamony Archana P. , Chan Chia-Ling , McFarland Andrea , Junankar Simon , Ye Sunny , Yang Jessica , Nikolic Iva , Shah Jaynish S. , Baker Laura A. , Millar Ewan K. A. , Naylor Matthew J. , Ormandy Christopher J. , Lakhani Sunil R. , Kaplan Warren , Mellick Albert S. , O'Toole Sandra A. , Swarbrick Alexander , Nair Radhika TITLE=Id Proteins Promote a Cancer Stem Cell Phenotype in Mouse Models of Triple Negative Breast Cancer via Negative Regulation of Robo1 JOURNAL=Frontiers in Cell and Developmental Biology VOLUME=8 YEAR=2020 URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2020.00552 DOI=10.3389/fcell.2020.00552 ISSN=2296-634X 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.