Poster Presentation 29th Lorne Cancer Conference 2017

Identification of a myoepithelial protein that suppresses the DCIS to invasive carcinoma transition in breast cancer (#151)

Hendrika M Duivenvoorden 1 , Laura E Edgington-Mitchell 2 , Elizabeth Robbins 3 , Bonnie F Sloane 4 5 , Sandra O'Toole 3 6 , Belinda S Parker 1
  1. Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, Bundoora, VIC, Australia
  2. Drug Discovery Biology, Monash Institute of Pharmaceutical Science, Melbourne, VIC, Australia
  3. Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia
  4. Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, USA
  5. Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA
  6. Garvan Institute, Darlinghurst, NSW, Australia

Due to the recent increased use of mammographic screening, between 15-25% of newly diagnosed breast cancers are actually at an early pre-invasive stage called ductal carcinoma in situ (DCIS). It is currently very difficult to predict which DCIS lesions will progress to invasive carcinoma and therefore prognostic markers are needed to predict invasive cancer risk and to individualise patient treatment. Myoepithelial cells represent a distinguishing barrier between DCIS and invasive breast carcinoma. We have identified that the cysteine protease inhibitor stefin A is highly expressed in myoepithelial cells surrounding normal ducts, and analysis of 800 DCIS areas revealed that stefin A is lowest in the myoepithelial cells surrounding higher grade DCIS lesions, those that are associated with an increased risk of invasive carcinoma recurrence.

To study the functional role of myoepithelial stefin A, a 3D co-culture model was developed whereby myoepithelial cells reverted the invasive potential of the MDA-MB-231 breast cancer cell line to a DCIS-like state. Reduced stefin A expression in N1ME myoepithelial cells reversed this effect and allowed MDA-MB-231 invasion despite the presence of the myoepithelial layer. Further studies exposed a potential role for cysteine cathepsin-mediated degradation of cell adherence proteins in this phenotype. A role for cathepsin inhibition in early stage tumorigenesis was also observed in vivo. Treatment of the MMTV-PyMT spontaneous mammary tumour mouse model with the cathepsin B specific inhibitor CA-074, reduced the development of invasive carcinoma.

Our studies suggest that stefin A expression in myoepithelial cells protects from invasion. Future validation could lead to myoepithelial stefin A being used as a prognostic marker to predict risk of invasive relapse in patients and therefore identify those that could be spared unnecessary therapeutic intervention.