Imperial College London
Alternate

ProfessorJonathanWaxman

Faculty of Medicine, Department of Surgery & Cancer

Emeritus Professor of Oncology
 
 
 
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j.waxman

 
 
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Location

 

ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Alshaker:2014:10.1186/s13058-014-0426-6,
author = {Alshaker, H and Krell, J and Frampton, AE and Waxman, J and Blyuss, O and Zaikin, A and Winkler, M and Stebbing, J and Yaguee, E and Pchejetski, D},
doi = {10.1186/s13058-014-0426-6},
journal = {Breast Cancer Research},
title = {Leptin induces upregulation of sphingosine kinase 1 in oestrogen receptor-negative breast cancer via Src family kinase-mediated, janus kinase 2-independent pathway},
url = {http://dx.doi.org/10.1186/s13058-014-0426-6},
volume = {16},
year = {2014}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Introduction: Obesity is a known risk factor for breast cancer. Sphingosine kinase 1 (SK1) is an oncogenic lipidkinase that is overexpressed in breast tumours and linked with poor prognosis, however, its role in obesity-drivenbreast cancer was never elucidated.Methods: Human primary and secondary breast cancer tissues were analysed for SK1 and leptin receptorexpression using quantitative real-time polymerase chain reaction (qRT-PCR) assay. Leptin-induced signalling wasanalysed in human oestrogen receptor (ER)-positive and negative breast cancer cells using Western blotting,qRT-PCR and radiolabelling assays.Results: Our findings show for the first time that human primary breast tumours and associated lymph nodemetastases exhibit a strong correlation between SK1 and leptin receptor expression (Pearson R = 0.78 and R = 0.77,respectively, P <0.001). Both these genes are elevated in metastases of ER-negative patients and show a significantincrease in patients with higher body mass index (BMI). Leptin induces SK1 expression and activation in ER-negativebreast cancer cell lines MDAMB-231 and BT-549, but not in ER-positive cell lines. Pharmacological inhibition andgene knockdown showed that leptin-induced SK1 activity and expression are mediated by activation of extracellularsignal-regulated kinases 1/2 (ERK1/2) and Src family kinase (SFK) pathways, but not by the major pathwaysdownstream of leptin receptor (LEPR) - janus kinase 2 (JAK2) and signal transducer and activator of transcription 3(STAT3). Src-homology 2 domain-containing phosphatase 2 (SHP2) appeared to be key to SK1 activation, and mayfunction as an adaptor protein between SFKs and LEPR. Importantly, leptin-induced breast cancer cell proliferationwas abrogated by SK1-specific small interfering RNA (siRNA).Conclusions: Overall, our findings demonstrate a novel SFK/ERK1/2-mediated pathway that links leptin signallingand expression of oncogenic enzyme SK1 in breast tumours and suggest the potential significance
AU  - Alshaker,H
AU  - Krell,J
AU  - Frampton,AE
AU  - Waxman,J
AU  - Blyuss,O
AU  - Zaikin,A
AU  - Winkler,M
AU  - Stebbing,J
AU  - Yaguee,E
AU  - Pchejetski,D
DO  - 10.1186/s13058-014-0426-6
PY  - 2014///
SN  - 1465-542X
TI  - Leptin induces upregulation of sphingosine kinase 1 in oestrogen receptor-negative breast cancer via Src family kinase-mediated, janus kinase 2-independent pathway
T2  - Breast Cancer Research
UR  - http://dx.doi.org/10.1186/s13058-014-0426-6
UR  - http://hdl.handle.net/10044/1/29185
VL  - 16
ER  -
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