Inhibitor of Differentiation 4 (ID4) represses mammary myoepithelial differentiation via inhibition of HEB
Holly Holliday,
Daniel Roden,
Simon Junankar,
Sunny Z. Wu,
Laura A. Baker,
Christoph Krisp,
Chia-Ling Chan,
Andrea McFarland,
Joanna N. Skhinas,
Thomas R. Cox,
Bhupinder Pal,
Nicholas D. Huntington,
Christopher J. Ormandy,
Jason S. Carroll,
Jane Visvader,
Mark P. Molloy,
Alexander Swarbrick
Affiliations
Holly Holliday
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia
Daniel Roden
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia
Simon Junankar
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia
Sunny Z. Wu
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia
Laura A. Baker
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia
Christoph Krisp
Australian Proteome Analysis Facility, Macquarie University, Sydney, NSW 2109, Australia; Institute of Clinical Chemistry and Laboratory Medicine, Mass Spectrometric Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany
Chia-Ling Chan
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
Andrea McFarland
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
Joanna N. Skhinas
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
Thomas R. Cox
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia
Bhupinder Pal
ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, VIC 3084, Australia
Nicholas D. Huntington
Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3168, Australia
Christopher J. Ormandy
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia
Jason S. Carroll
Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK
Jane Visvader
ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia
Mark P. Molloy
Australian Proteome Analysis Facility, Macquarie University, Sydney, NSW 2109, Australia
Alexander Swarbrick
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia; Corresponding author
Summary: Inhibitor of differentiation (ID) proteins dimerize with basic HLH (bHLH) transcription factors, repressing transcription of lineage-specification genes across diverse cellular lineages. ID4 is a key regulator of mammary stem cells; however, the mechanism by which it achieves this is unclear. Here, we show that ID4 has a cell autonomous role in preventing myoepithelial differentiation of basal cells in mammary organoids and in vivo. ID4 positively regulates proliferative genes and negatively regulates genes involved in myoepithelial function. Mass spectrometry reveals that ID4 interacts with the bHLH protein HEB, which binds to E-box motifs in regulatory elements of basal developmental genes involved in extracellular matrix and the contractile cytoskeleton. We conclude that high ID4 expression in mammary basal stem cells antagonizes HEB transcriptional activity, preventing myoepithelial differentiation and allowing for appropriate tissue morphogenesis. Downregulation of ID4 during pregnancy modulates gene regulated by HEB, promoting specialization of basal cells into myoepithelial cells.
