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

Richard D A Wilkinson,Roberta E Burden,Christopher J Scott,Richard D Kennedy,Nuala Mccabe,Victoria Bingham,Stephen Mcquaid,Rich Williams,Órla T Cox,Niamh E Buckley,Rosemary O’Connor,Darragh G Mcart,Sara H Mcdowell

doi:10.1155/2019/3980273

Richard D A Wilkinson, Roberta E Burden + Show 11 more

Open Access

https://doi.org/10.1155/2019/3980273

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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.

Highlights

Breast cancer is a highly heterogeneous disease and may be classified into different sub-types which affects treatment approach and patient prognosis [1]
There was a significant association between high Cathepsin S (CTSS) expression, and increased tumour stage (p=0.035) in the
This investigation began by observing differences in patient outcome based on CTSS expression, with stromal-associated CTSS expression shown to be associated with a poor outcome, whereas high CTSS expression in epithelial cells is associated with an improved outcome

Summary

Introduction

Breast cancer is a highly heterogeneous disease and may be classified into different sub-types which affects treatment approach and patient prognosis [1]. Classification of breast cancer has been assigned via the presence/absence of the estrogen receptor (ER) or HER2 amplification, which allow use of targeted treatments such as tamoxifen and trastuzumab, respectively. Tumour cells lacking these receptors, in addition to the progesterone receptor (PR), are termed “triple negative” (TNBC) and have the poorest outcome due in part to the lack of targeted therapies available. Despite a high rate of response to chemotherapy, TNBC is associated with high rates of relapse and death [2].

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