Characterisation of the protease Cathepsin S as a novel therapeutic target in Triple-Negative Breast Cancer

  • Sara McDowell

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

Triple-Negative Breast Cancer (TNBC) is an aggressive breast cancer subtype. Cathepsin S (CatS) is a lysosomal protease, overexpressed in multiple cancer types. Preliminary studies revealed in TNBC cells with BRCA1 dysfunction, CatS expression was elevated. It was hypothesised that BRCA1 dysfunction in TNBC contributed to increased CatS expression, and this promoted TNBC invasion and metastasis. 4T1 shBRCA1, shCatS, and CatS overexpressing cell lines were developed. Increased CatS expression in the shBRCA1 and CatS overexpressing cells increased invasion in vitro. shCatS cells or CatS inhibitor treatment reduced this invasiveness, showing that CatS contributed to driving invasion in vitro. 4T1 shBRCA1 and 4T1 shCatS cells were used in syngeneic mammary implant in vivo models to study the impact on primary tumour growth and metastasis. RNA-Seq analysis of 4T1 shBRCA1 and 4T1 shCatS cell lines was performed for differential gene expression analysis. Finally, three TNBC patient TMA cohorts were tested to examine CatS expression in relation to patient survival outcomes as well as differences in immune cell infiltrate.

This thesis is embargoed until 31 July 2029.
Date of AwardJul 2024
Original languageEnglish
Awarding Institution
  • Queen's University Belfast
SponsorsBreast Cancer Now
SupervisorRoberta Burden (Supervisor), Christopher Scott (Supervisor) & Niamh Buckley (Supervisor)

Keywords

  • cathepsin s
  • TNBC
  • protease
  • triple-negative breast cancer
  • tumour microenvironment

Cite this

'