TGFβ-mediated MMP13 secretion drives myoepithelial cell dependent breast cancer progression
Institution: Barts Cancer Institute, Queen Mary University of London
Corresponding Researcher: Richard Grose
Data Link(s): All RNAseq data generated during the study are publicly available and have been deposited in Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/) with the accession code GSE224401. Invasive Breast Carcinoma data are available on cBioportal (https://www.cbioportal.org) and were generated by the TCGA research Network (https://www.cancer.gov/tcga). EP300 Kaplan-Meier plots were generated with Kaplan-Meier Plotter (https://kmplot.com) using proteomic data available in the PRIDE Archive - proteomics data repository under the accession number PXD005692. All further datasets generated and analysed in this study are available from the corresponding author upon reasonable request.
Keyword(s): 3D in vitro model, ductal carcinoma in situ, luminal cells, myoepithelial cells
Summary
Ductal 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 TGFβ - 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.
