Breast cancer is now diagnosed in 1 in 8 women in their lifetime. Due to mammographic screening, approximately 25% of breast cancers are diagnosed at an early stage that has not yet invaded the breast tissue, termed ductal carcinoma in situ (DCIS). Progression of DCIS to invasive ductal carcinoma (IDC) significantly increases the risk of tumour cell dissemination and metastasis, however it is currently very difficult to accurately predict patients that will develop invasive cancer and this is important to discriminate patients that are at low risk and can be spared therapy, commonly radiotherapy.
Myoepithelial cells are spindle shaped cells that surround the ducts of the breast and produce the basement membrane. Disruption of this myoepithelial boundary is a hallmark of the DCIS to IDC transition. Investigations in our laboratory have revealed that stefin A, a cysteine cathepsin inhibitor, is expressed abundantly in the myoepithelial cells surrounding normal ducts. Previous research in the laboratory has revealed that stefin A is a metastasis suppressor and that expression of stefin A in invasive primary tumours predicted a favourable outcome in patients. Analysis of stefin A myoepithelial expression in patient tissues has revealed a loss in high grade DCIS lesions, those most likely to progress to invasive disease. Using 3D models developed in our laboratory that mimic the DCIS-like state, we have confirmed a functional role of myoepithelial stefin A in suppressing the DCIS to invasive transition. Loss of stefin A in N1ME myoepithelial cells promoted MDA-MB-231 invasion, an effect that was reverted with the addition of pharmacological cathepsin inhibitors. The role of cathepsin inhibitors in suppressing early tumorigenesis was also confirmed in the MMTV-PyMT model.
Current studies aim to validate myoepithelial stefin A as a marker of reduced risk of local and distant cancer relapse and identifying the key mechanisms behind its suppressive role in myoepithelial cells.