Myoepithelial cell-specific expression of stefin A as a suppressor of early breast cancer invasion

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

Research output: Contribution to journalArticleResearchpeer-review

21 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)496-509
Number of pages14
JournalJournal of Pathology
Volume243
Issue number4
DOIs
Publication statusPublished - 1 Dec 2017

Keywords

  • 3D culture
  • breast cancer
  • cystatin A
  • cysteine cathepsins
  • myoepithelial cells
  • stefin A

Cite this

Duivenvoorden, H. M., Rautela, J., Edgington-Mitchell, L. E., Spurling, A., Greening, D. W., Nowell, C. J., Molloy, T. J., Robbins, E., Brockwell, N. K., Lee, C. S., Chen, M., Holliday, A., Selinger, C. I., Hu, M., Britt, K. L., Stroud, D. A., Bogyo, M., Möller, A., Polyak, K., ... Parker, B. S. (2017). Myoepithelial cell-specific expression of stefin A as a suppressor of early breast cancer invasion. Journal of Pathology, 243(4), 496-509. https://doi.org/10.1002/path.4990