Abstract
The relative roles of SULF1 and SULF2 enzymes in tumour growth are controversial, but short SULF1/SULF2 splice variants predominate in human mammary tumours despite their non-detectable levels in normal mammary tissue. Compared with the normal, the level of receptor tyrosine kinase (RTK) activity was markedly increased in triple-positive mammary tumours during later stages of tumour progression showing increased p-EGFR, p-FGFR1 and p-cMet activity in triple-positive but not in triple-negative tumours. The abundance of catalytically inactive short SULF1/SULF2 variants permits high levels of HS sulphation and thus growth driving RTK cell signalling in primary mammary tumours. Also observed in this study, however, was increased N-sulphation detected by antibody 10E4 indicating that not only 6-O sulphation but also N-sulphation may contribute to increased RTK cell signalling in mammary tumours. The levels of such increases in not only SULF1/SULF2 but also in pEGFR, pFGFR1, p-cMet and Smad1/5/8 signalling were further enhanced following lymph node metastasis. The over-expression of Sulf1 and Sulf2 variants in mammary tumour-derived MDA-MB231 and MCF7 cell lines by transfection further confirms Sulf1-/Sulf2-mediated differential modulation of growth. The short variants of both Sulf1 and Sulf2 promoted FGF2-induced MDA-MB231 and MCF7 in vitro growth while full-length Sulf1 inhibited growth supporting in vivo mammary tumour cell signalling patterns of growth. Since a number of mammary tumours become drug resistant to hormonal therapy, Sulf1/Sulf2 inhibition could be an alternative therapeutic approach to target such tumours by down-regulating RTK-mediated cell signalling.
Highlights
Mammary tumours represent the most common cancer amongst women but like many other cancers it is molecularly heterogeneous and highly variable in its therapeutic response and metastatic properties (Engstrøm MJ et al 2013)
SULF2 expression is observed in all mammary tumours the level of this enzyme was lower in triple positive compared with triple negative tumours (Figure 2)
The level of SULF1 in triple positive tissues was considerably higher than levels of SULF2 in such tumours while both SULF1 and SULF2 predominated in triple negative samples
Summary
Mammary tumours represent the most common cancer amongst women but like many other cancers it is molecularly heterogeneous and highly variable in its therapeutic response and metastatic properties (Engstrøm MJ et al 2013). Targeting co-receptors such as heparan sulfate proteoglycans (HSPGs) or their modifying enzymes may inhibit multiple cancer signalling pathways considering that the expression of HSPGs and their associated enzymes markedly change during tumour growth. Heparan sulfate (HS) chains of glycosaminoglycans (GAGs) in HSPGs are made up of repeating disaccharide units of glucuronic/iduronic acid and glucosamine that show further modifications of their properties generated by deacetylation, epimerization and sulfation at the N-, 3-O, and 6-O positions of glucosamine and the 2-O position of the iduronic acid residue Changes in their HS sulfation patterns can exert differential functional effects on cell signalling and drive regulated normal development and dysregulated tumour growth. Sulf1/Sulf regulation of 6-O HS sulfation has the potential to control cell growth and migration by regulating the activities of specific cell signaling pathways
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