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Id Proteins Promote a Cancer Stem Cell Phenotype in Triple Negative Breast

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Id Proteins Promote a Cancer Stem Cell Phenotype in Triple Negative Breast bioRxiv preprint doi: https://doi.org/10.1101/497313; this version posted March 11, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. 1 Id proteins promote a cancer stem cell phenotype in triple negative 2 breast cancer via negative regulation of Robo1 3 Wee S. Teo1,2, Holly Holliday1,2#, Nitheesh Karthikeyan3#, Aurélie S. Cazet1,2, Daniel L. 4 Roden1,2, Kate Harvey1, Christina Valbirk Konrad1, Reshma Murali3, Binitha Anu Varghese3, 5 Archana P. T.3,4, Chia-Ling Chan1,2, Andrea McFarland1, Simon Junankar1,2, Sunny Ye1, 6 Jessica Yang1, Iva Nikolic1,2, Jaynish S. Shah5, Laura A. Baker1,2, Ewan K.A. Millar1,6,7,8, 7 Mathew J. Naylor1,2,10, Christopher J. Ormandy1,2, Sunil R. Lakhani11, Warren Kaplan1,12, 8 Albert S. Mellick13,14, Sandra A. O’Toole1,9, Alexander Swarbrick1,2*, Radhika Nair1,2,3* 9 Affiliations 10 1Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia 11 2St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, New South Wales, 12 Australia 13 3 Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Kerala, India 14 4Manipal Academy of Higher Education, Manipal, Karnataka, India 15 5Centenary Institute, The University of Sydney, New South Wales, Australia 16 6 Department of Anatomical Pathology, NSW Health Pathology, St George Hospital, 17 Kogarah, NSW, Australia 18 7 School of Medical Sciences, UNSW Sydney, Kensington NSW, Australia. 19 8 School of Medicine, Western Sydney University, Locked Bag 1797, Penrith, NSW, 20 Australia 21 9Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, 22 Camperdown, NSW, Australia 23 10Discipline of Physiology & Bosch Institute, School of Medical Sciences, University of 24 Sydney, NSW, Australia 25 11The University of Queensland, UQ Centre for Clinical Research, School of Medicine and 26 Pathology Queensland, Royal Brisbane & Women’s Hospital, Herston, Brisbane, 27 Queensland, Australia 28 12Peter Wills Bioinformatics Centre, Garvan Institute of Medical Research, Darlinghurst, 29 NSW, Australia 30 13UNSW Medicine, University of NSW, 18 High St, Kensington, NSW, Australia. 31 14Ingham Institute for Applied Medical Research, 1 Campbell Street, Liverpool, NSW, 32 Australia. 33 34 35 # These authors contributed equally 36 37 38 Number of words: 5,552 39 Number of figures: 5 40 Number of tables: 3 41 Number of supplementary figures: 4 42 Number of supplementary tables: 7 1 bioRxiv preprint doi: https://doi.org/10.1101/497313; this version posted March 11, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. 43 * Co-corresponding authors 44 * Dr Radhika Nair 45 Present address 46 Rajiv Gandhi Centre for Biotechnology 47 Kerala 695014, India 48 [email protected] 49 Phone: +91-471-2781251 50 Fax: +91-471-2346333 51 52 * A/Prof Alexander Swarbrick 53 Cancer Research Division, Garvan Institute of Medical Research 54 370 Victoria St, Darlinghurst, NSW, 2010 55 Australia 56 [email protected] 57 Phone: +61-2-9355-5780 58 Fax: +61-2-355-5869 59 60 Running title: Id-Robo1 axis in TNBC 61 62 2 bioRxiv preprint doi: https://doi.org/10.1101/497313; this version posted March 11, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. 63 Abstract 64 Breast cancers display phenotypic and functional heterogeneity and several lines of evidence 65 support the existence of cancer stem cells (CSCs) in certain breast cancers, a minor 66 population of cells capable of tumor initiation and metastatic dissemination. Identifying 67 factors that regulate the CSC phenotype is therefore important for developing strategies to 68 treat metastatic disease. The Inhibitor of Differentiation Protein 1 (Id1) and its closely related 69 family member Inhibitor of Differentiation 3 (Id3) (collectively termed Id) are expressed by a 70 diversity of stem cells and are required for metastatic dissemination in experimental models 71 of breast cancer. In this study, we show that ID1 is expressed in rare neoplastic cells within 72 ER-negative breast cancers. To address the function of Id1 expressing cells within tumors, we 73 developed two independent murine models of Triple Negative Breast Cancer (TNBC) in 74 which a genetic reporter permitted the prospective isolation of Id1+ cells. Id1+ cells are 75 enriched for self-renewal in tumorsphere assays in vitro and for tumor initiation in vivo. 76 Conversely, depletion of Id1 and Id3 in the 4T1 murine model of TNBC demonstrates that 77 Id1/3 are required for cell proliferation and self-renewal in vitro, as well as primary tumor 78 growth and metastatic colonization of the lung in vivo. Using combined bioinformatic 79 analysis, we have defined a novel mechanism of Id protein function via negative regulation of 80 the Roundabout Axon Guidance Receptor Homolog 1 (Robo1) leading to activation of a Myc 81 transcriptional programme. 82 83 Key words: Id proteins, Robo1, Cancer stem cell, Metastasis, Myc signature 3 bioRxiv preprint doi: https://doi.org/10.1101/497313; this version posted March 11, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. 84 Introduction 85 Several lines of evidence suggest that rare sub-populations of tumor cells, commonly termed 86 cancer stem cells (CSCs), drive key tumor phenotypes such as self-renewal, drug resistance 87 and metastasis and contribute to disease relapse and associated patient mortality (Chen et al., 88 2012; Lawson et al., 2015; Li et al., 2008; Malanchi et al., 2011). Recent evidence points to 89 the hypothesis that CSCs are not static, but they exist in dynamic states, driven by critical 90 transcription factors and are highly dependent on the microenvironmental cues (da Silva-Diz 91 et al., 2018; Lee et al., 2016b; Wahl and Spike, 2017). Understanding the molecular networks 92 that are critical to the survival and plasticity of CSCs is fundamental to resolving clinical 93 problems associated with chemo-resistance and metastatic residual disease. 94 The Inhibitor of DNA binding (ID) proteins have previously been recognized as regulators of 95 CSCs and tumor progression (Lasorella et al., 2014). These proteins constitute a family of 96 four highly conserved transcriptional regulators (ID1-4) that act as dominant-negative 97 inhibitors of basic helix–loop–helix (bHLH) transcription factors. ID proteins are expressed 98 in a tissue-specific and stage-dependent manner and are required for the maintenance of self- 99 renewal and multipotency of embryonic and many tissue stem cells (Aloia et al., 2015; Hong 100 et al., 2011; Liang et al., 2009; Stankic et al., 2013) . Previous studies have reported a 101 functional redundancy among the four members of the mammalian Id family, in particular 102 Id1 and Id3 (referred to collectively here as Id), and their overlapping expression patterns 103 during normal development and cancer (Anido et al., 2010; Gupta et al., 2007; Lyden et al., 104 1999; Niola et al., 2013; O'Brien et al., 2012). Id2 and Id4 were not investigated in this work 105 as they are found to have independent functions from Id1 and Id3. 106 A number of studies have implied a significant role for ID1 and ID3 in breast cancer 107 progression and metastasis (Gupta et al., 2007). We have previously demonstrated that Id1 108 cooperates with activated Ras signalling and promotes mammary tumor initiation and 109 metastasis in vivo by supporting long-term self-renewal and proliferative capacity (Swarbrick 110 et al., 2008). Additional work has clearly implicated ID1 in regulating D- and E-type cyclins 111 and their associated cyclin-dependant kinases, CDK4 and CDK2 in human breast epithelial 112 cells , p21 (Swarbrick et al., 2005), the matrix metalloproteinase MT1-MMP (Fong et al., 113 2003), KLF17 (Gumireddy et al., 2009), Cyclin D1 (Tobin et al., 2011), Bcl-2 (Kim et al., 114 2008), and BMI1 (Qian et al., 2010) among others. 115 Even though several Id-dependent targets have been identified, we still lack a comprehensive 116 picture of the downstream molecular mechanisms controlled by Id and their associated 117 pathways mediating breast cancer progression and metastasis particularly in the poor 118 prognostic TNBC subtype. In this study, we demonstrate using four independent mouse 119 models of TNBC that Id is important for the maintenance of a CSC phenotype. We also 120 describe a novel mechanism by which Id controls the CSC state by negatively regulating 121 Robo1 to control proliferation and self-renewal via indirect activation of a Myc 122 transcriptional programme. 123 124 125 126 127 4 bioRxiv preprint doi: https://doi.org/10.1101/497313; this version posted March 11, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. 128 Materials and Methods 129 Plasmids 130 pEN_TmiRc3 parental entry plasmid, pSLIK-Venus and pSLIK-Neo destination vectors were 131 obtained from the ATCC (Manassas, VA,USA). 132 Cell culture 133 4T1 and HEK293T cells were obtained from the American Type Culture Collection (ATCC).
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