Triple negative breast cancer is associated with poor prognosis due to its propensity to recur in a metastatic and chemotherapy-resistant form. Tumour-initaitng cells (TICs) are highly specialized cancer cell populations responsible for tumour progression, metastasis and chemotherapy-resistance. TICs can be identified by a CD44Hi cell phenotype, and by expression of Epithelial-Mesenchymal Transition transcription factors (EMT-TFs), including ZEB1 and SNAI1. Our research demonstrates TICs undergo bi-directional conversions between the TIC and the non-TIC cell state.
By comparing gene expression profiles we discovered that the enzyme sulfatase 1 (SULF1) is upregulated in TICs compared to their non-TIC counterparts and that expression is tightly correlated to that of ZEB1. SULF1 is an extracellular sulfatase that controls the sulfation pattern of heparan sulphate proteoglycans (HSPGs) present on the cell surface and in the extracellular matrix. By removing 6-0-sulfation from HSPGs, SULF1 regulates growth factor availability and subsequently affects multiple signalling cascades that regulate cancer cell proliferation, migration and angiogenesis.
Database analysis shows that SULF1 is also overexpressed in basal-type (including triple-negative) breast cancers compared to control tissue, and that high SULF1 expression correlates with poor survival. We demonstrate that SULF1 loss inhibits tumour-initiating potential by reducing primary tumour volume. Furthermore, SULF1 downregulation abolished metastasis too, suggesting SULF1 may be a novel target for therapeutic intervention. We demonstrate that SULF1 knock-down in vivo induced a downregulation of the EMT-TF SNAI1 and an upregulation of the epithelial marker E-Cadherin suggesting that SULF1 loss forces TICs into a more epithelial, non-aggressive state.
We are currently investigating the SULF1-driven signalling networks that promote the TIC state that drives triple-negative breast cancer progression, metastasis and chemotherapy-resistance. We aim to derive novel therapeutic strategies to improve patient outcome.