Gibson, Shayin V.Tomas Bort, ElenaRodriguez-Fernandez, LuciaAllen, Michael D.Gomm, Jennifer J.Goulding, IainKeller, Ulrich Auf DemAgnoletto, AndreaBrisken, CathrinPeck, BarrieCameron, Angus J.Marshall, John F.Jones, J. LouiseCarter, Edward P.Grose, Richard P.2023-04-102023-04-102023-04-102023-03-0210.1038/s41523-023-00513-6https://infoscience.epfl.ch/handle/20.500.14299/196821WOS:000942808900001Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer. Virtually all women with DCIS are treated, despite evidence suggesting up to half would remain with stable, non-threatening, disease. Overtreatment thus presents a pressing issue in DCIS management. To understand the role of the normally tumour suppressive myoepithelial cell in disease progression we present a 3D in vitro model incorporating both luminal and myoepithelial cells in physiomimetic conditions. We demonstrate that DCIS-associated myoepithelial cells promote striking myoepithelial-led invasion of luminal cells, mediated by the collagenase MMP13 through a non-canonical TGF beta - EP300 pathway. In vivo, MMP13 expression is associated with stromal invasion in a murine model of DCIS progression and is elevated in myoepithelial cells of clinical high-grade DCIS cases. Our data identify a key role for myoepithelial-derived MMP13 in facilitating DCIS progression and point the way towards a robust marker for risk stratification in DCIS patients.Oncologycarcinoma in-situgrowth-factor requirementshuman mammary-glandcollagenase-3 expressionalpha-v-beta-6 integrintumor microenvironmentcollective invasionepithelial-cellsactivationdcistext::journal::journal article::research article