A proteolytic landscape: understanding the role of myoepithelial cells in early-stage breast cancer progression
Institution: Barts Cancer Institute, Queen Mary University of London
Corresponding Researcher: Richard Grose
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Summary
Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer. Despite evidence suggesting that up to half of DCIS cases would remain stable and non-threatening, virtually all women with DCIS are treated, highlighting overtreatment as a pressing issue in DCIS management. To understand the role of the tumour-associated myoepithelium, we present a 3D in vitro model that incorporates both luminal and myoepithelial cells in physiomimetic conditions. We demonstrate that integrin β6-expressing DCIS-associated myoepithelial cells promote striking myoepithelial-led invasion of luminal cells via upregulation of 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. In addition to the upregulation of tumour-promoting MMP13, we also demonstrate the repressive function of myoepithelial ADAMTS3, with increased invasion observed upon ADAMTS3 siRNA-mediated loss. Degradomic analysis, using a terminal amine isotopic labelling of substrates approach, combined with functional assays, implicate fibronectin as a direct ADAMTS3 substrate. We further show that loss of ADAMTS3 enhances fibronectin levels in the microenvironment and promotes invasion through canonical integrin α5β1 activation. Our data identify a key role for myoepithelial-derived MMP13 and ADAMTS3 loss in facilitating DCIS progression, pointing the way towards robust markers for risk stratification in DCIS patients.
