Leptin induces upregulation of sphingosine kinase 1 in oestrogen receptor-negative breast cancer via Src family kinase-mediated, janus kinase 2-independent pathway.

Abstract

INTRODUCTION:

Obesity is a known risk factor for breast cancer. Sphingosine kinase 1 (SK1) is an oncogenic lipid kinase that is overexpressed in breast tumours and linked with poor prognosis, however, its role in obesity-driven breast cancer was never elucidated.

METHODS:

Human primary and secondary breast cancer tissues were analysed for SK1 and leptin receptor expression using quantitative real-time polymerase chain reaction (qRT-PCR) assay. Leptin-induced signalling was analysed 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 node metastases 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 significant increase in patients with higher body mass index (BMI). Leptin induces SK1 expression and activation in ER-negative breast cancer cell lines MDAMB-231 and BT-549, but not in ER-positive cell lines. Pharmacological inhibition and gene knockdown showed that leptin-induced SK1 activity and expression are mediated by activation of extracellular signal-regulated kinases 1/2 (ERK1/2) and Src family kinase (SFK) pathways, but not by the major pathways downstream 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 may function as an adaptor protein between SFKs and LEPR. Importantly, leptin-induced breast cancer cell proliferation was abrogated by SK1-specific small interfering RNA (siRNA).

CONCLUSIONS:

Overall, our findings demonstrate a novel SFK/ERK1/2-mediated pathway that links leptin signalling and expression of oncogenic enzyme SK1 in breast tumours and suggest the potential significance of this pathway in ER-negative breast cancer.

• Authors: Heba Alshaker, Jonathan Krell, Adam E Frampton, Jonathan Waxman, Oleg Blyuss, Alexey Zaikin, Mathias Winkler, Justin Stebbing, Ernesto Yagüe, Dmitri Pchejetski
• Journal: Breast cancer research : BCR (Breast Cancer Res) Vol. 16 Issue 5 Pg. 426 (Oct 25 2014) ISSN: 1465-542X [Electronic] England
• PMID: 25482303 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• LEPR protein, human
• Leptin
• Receptors, Estrogen
• Receptors, Leptin
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• Phosphotransferases (Alcohol Group Acceptor)
• sphingosine kinase
• JAK2 protein, human
• Janus Kinase 2
• src-Family Kinases
• Protein Tyrosine Phosphatase, Non-Receptor Type 11

Topics

• Breast Neoplasms (etiology, metabolism, pathology)
• Cell Proliferation
• Enzyme Induction
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Janus Kinase 2 (metabolism)
• Leptin (physiology)
• Lymphatic Metastasis
• MCF-7 Cells
• Obesity (complications, metabolism)
• Phosphorylation
• Phosphotransferases (Alcohol Group Acceptor) (genetics, metabolism)
• Protein Processing, Post-Translational
• Protein Tyrosine Phosphatase, Non-Receptor Type 11 (metabolism)
• Receptors, Estrogen (metabolism)
• Receptors, Leptin (metabolism)
• Signal Transduction
• Up-Regulation
• Vascular Endothelial Growth Factor A (metabolism)
• src-Family Kinases