A Novel Role for Cathepsin S as a Potential Biomarker in Triple Negative Breast Cancer

Abstract

Cathepsin S (CTSS) has previously been implicated in a number of cancer types, where it is associated with poor clinical features and outcome. To date, patient outcome in breast cancer has not been examined with respect to this protease. Here, we carried out immunohistochemical (IHC) staining of CTSS using a breast cancer tissue microarray in patients who received adjuvant therapy. We scored CTSS expression in the epithelial and stromal compartments and evaluated the association of CTSS expression with matched clinical outcome data. We observed differences in outcome based on CTSS expression, with stromal-derived CTSS expression correlating with a poor outcome and epithelial CTSS expression associated with an improved outcome. Further subtype characterisation revealed high epithelial CTSS expression in TNBC patients with improved outcome, which remained consistent across two independent TMA cohorts. Further in silico gene expression analysis, using both in-house and publicly available datasets, confirmed these observations and suggested high CTSS expression may also be beneficial to outcome in ER-/HER2+ cancer. Furthermore, high CTSS expression was associated with the BL1 Lehmann subgroup, which is characterised by defects in DNA damage repair pathways and correlates with improved outcome. Finally, analysis of matching IHC analysis reveals an increased M1 (tumour destructive) polarisation in macrophage in patients exhibiting high epithelial CTSS expression. In conclusion, our observations suggest epithelial CTSS expression may be prognostic of improved outcome in TNBC. Improved outcome observed with HER2+ at the gene expression level furthermore suggests CTSS may be prognostic of improved outcome in ER- cancers as a whole. Lastly, from the context of these patients receiving adjuvant therapy and as a result of its association with BL1 subgroup CTSS may be elevated in patients with defects in DNA damage repair pathways, indicating it may be predictive of tumour sensitivity to DNA damaging agents.

Integrative Identification of Hub Genes Associated With Immune Cells in Atrial Fibrillation Using Weighted Gene Correlation Network Analysis

“…In chronic obstructive pulmonary disease, reduction in CTSS expression prevents loss of lung function, reduces inflammation, and slows the lung tissue remodeling ( 31 ). Moreover, CTSS was identified as novel biomarkers for diseases and physiological processes, including triple-negative breast cancer, sarcoidosis, and particulate-induced lysosomal disruption in macrophages ( 32 – 34 ).…”

Glucocorticoid Receptor Expression Predicts Good Outcome in response to Taxane-Free, Anthracycline-Based Therapy in Triple Negative Breast Cancer

“…e first TMA with matched samples to the in-house gene expression cohort has been previously described elsewhere [17,23]. e subsequent TMAs with various chemotherapy regimens have also been previously described [9,[24][25][26]. Clinical information from these TMAs is summarised in Table 1.…”

Complement inhibitor CSMD1 modulates epidermal growth factor receptor oncogenic signaling and sensitizes breast cancer cells to chemotherapy

“…In addition, CTSS protein expression was decreased by CSMD1, reflecting the low metastatic potential of these cells. Recently, CTSS was introduced as a potential biomarker in TNBC, while mechanistically contributing to BCC's ability to metastasize to the brain via a Src dependent mechanism [ 41 , 42 ]. In this study, we focused on the relation between CSMD1 and EGFR, considering the importance of EGFR in TNBC.…”