Biochemistry and Pharmacology - Research Publications

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Author: Britt, Kara × Author: Edgington-Mitchell, Laura × Author: Rautela, Jai × End date: 2018 ×

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    Myoepithelial cell-specific expression of stefin A as a suppressor of early breast cancer invasion
    Duivenvoorden, HM ; Rautela, J ; Edgington-Mitchell, LE ; Spurling, A ; Greening, DW ; Nowell, CJ ; Molloy, TJ ; Robbins, E ; Brockwell, NK ; Lee-, CS ; Chen, M ; Holliday, A ; Selinger, CI ; Hu, M ; Britt, KL ; Stroud, DA ; Bogyo, M ; Moeller, A ; Polyak, K ; Sloane, BF ; O'Toole, SA ; Parker, BS (WILEY, 2017-12)
    Mammography screening has increased the detection of early pre-invasive breast cancers, termed ductal carcinoma in situ (DCIS), increasing the urgency of identifying molecular regulators of invasion as prognostic markers to predict local relapse. Using the MMTV-PyMT breast cancer model and pharmacological protease inhibitors, we reveal that cysteine cathepsins have important roles in early-stage tumorigenesis. To characterize the cell-specific roles of cathepsins in early invasion, we developed a DCIS-like model, incorporating an immortalized myoepithelial cell line (N1ME) that restrained tumor cell invasion in 3D culture. Using this model, we identified an important myoepithelial-specific function of the cysteine cathepsin inhibitor stefin A in suppressing invasion, whereby targeted stefin A loss in N1ME cells blocked myoepithelial-induced suppression of breast cancer cell invasion. Enhanced invasion observed in 3D cultures with N1ME stefin A-low cells was reliant on cathepsin B activation, as addition of the small molecule inhibitor CA-074 rescued the DCIS-like non-invasive phenotype. Importantly, we confirmed that stefin A was indeed abundant in myoepithelial cells in breast tissue. Use of a 138-patient cohort confirmed that myoepithelial stefin A (cystatin A) is abundant in normal breast ducts and low-grade DCIS but reduced in high-grade DCIS, supporting myoepithelial stefin A as a candidate marker of lower risk of invasive relapse. We have therefore identified myoepithelial cell stefin A as a suppressor of early tumor invasion and a candidate marker to distinguish patients who are at low risk of developing invasive breast cancer, and can therefore be spared further treatment. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.