R M S Gill
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
Authors
V Mehra
E Milford
G K Dhoot
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 |
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 |
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