Poster Presentation 28th Lorne Cancer Conference 2016

THE ROLE OF STROMAL STEFIN A IN PREVENTING BREAST CANCER INVASION (#138)

Hendrika M Duivenvoorden 1 , Jai Rautela 1 , Laura E Edgington-Mitchell 2 , Timothy Molloy 3 4 , Elizabeth Robbins 5 , Matthew Bogyo 6 , Bonnie F Sloane 7 8 , Sandra O'Toole 3 9 , 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. Garvan Institute, Darlinghurst, NSW, Australia
  4. The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia
  5. St Vincent's Hospital, Darlinghurst, NSW, Australia
  6. Department of Pathology, Stanford University, School of Medicine, Stanford, California, USA
  7. Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, USA
  8. Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA
  9. Royal Prince Alfred Hospital, Camperdown, NSW, Australia

Early detection of breast cancer has resulted in an increase in patients diagnosed with ductal carcinoma in situ (DCIS), an early lesion that is associated with a favourable prognosis compared to patients diagnosed with invasive disease. A proportion of these patients later develop invasive disease and this is currently very difficult to predict. The key feature of DCIS is that cancer cells have not yet invaded beyond the myoepithelial cell barrier that surrounds breast ducts.  Disruption of this barrier is associated with progression to invasive carcinoma.

Stefin A, a cathepsin inhibitor, was expressed abundantly in the myoepithelial cells surrounding normal ducts. Immunohistochemical detection of stefin A expression in a cohort of normal, hyperplasia and DCIS tissues has revealed that stefin A expression is reduced or absent in myoepithelial cells surrounding high grade DCIS lesions compared to expression in normal or low grade DCIS lesions.  Importantly, the high grade DCIS lesions are more likely to progress to invasive carcinoma, hence the loss of stefin A in these ducts is an interesting result. 3D culturing revealed that human myoepithelial cells can revert the invasive phenotype of the highly metastatic MDA-MB-231 line, to a DCIS-like state. Importantly, stefin A knockdown in myoepithelial cells blocked this reversion, suggesting a key role of myoepithelial stefin A in blocking the DCIS to invasive carcinoma transition.

This project has demonstrated the importance of stefin A within the myoepithelial cells, and has suggested that this cathepsin inhibitor could have important value in predicting breast cancer relapse in patients diagnosed with DCIS.