Short SULF1/SULF2 splice variants predominate in mammary tumours with a potential to facilitate receptor tyrosine kinase-mediated cell signalling

Gill, R M S; Mehra, V; Milford, E; Dhoot, G K

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.

Citation

Gill, R. M. S., Mehra, V., Milford, E., & Dhoot, G. K. (2016). Short SULF1/SULF2 splice variants predominate in mammary tumours with a potential to facilitate receptor tyrosine kinase-mediated cell signalling. Histochemistry and Cell Biology, 146, 431-144. https://doi.org/10.1007/s00418-016-1454-3

• Journal Article Type: Article
• Acceptance Date: May 24, 2016
• Publication Date: Jun 13, 2016
• Deposit Date: Jun 11, 2016
• Publicly Available Date: Jun 11, 2016
• Journal: Histochemistry and Cell Biology
• Print ISSN: 0948-6143
• Electronic ISSN: 1432-119X
• Publisher: Springer
• Peer Reviewed: Peer Reviewed
• Volume: 146
• Pages: 431-144
• DOI: https://doi.org/10.1007/s00418-016-1454-3
• Public URL: https://rvc-repository.worktribe.com/output/1396487