Myoepithelial cell-specific expression of stefin A as a suppressor of early breast cancer invasion Academic Article uri icon


  • 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.


  • Duivenvoorden, Hendrika M
  • Rautela, Jai
  • Edgington-Mitchell, Laura E
  • Spurling, Alex
  • Greening, David W
  • Nowell, Cameron J
  • Molloy, Timothy J
  • Robbins, Elizabeth
  • Brockwell, Natasha K
  • Lee, Cheok Soon
  • Chen, Maoshan
  • Holliday, Anne
  • Selinger, Cristina I
  • Hu, Min
  • Britt, Kara L
  • Stroud, David A
  • Bogyo, Matthew
  • Möller, Andreas
  • Polyak, Kornelia
  • Sloane, Bonnie F
  • O'Toole, Sandra A
  • Parker, Belinda S

publication date

  • 2017

has subject area