Expression of sphingosine 1-phosphate receptor 4 and sphingosine kinase 1 is associated with outcome in oestrogen receptor-negative breast cancer

被引：55

作者：

Ohotski, J. ^{[2
]}

Long, J. S. ^{[2
]}

Orange, C. ^{[3
]}

Elsberger, B. ^{[3
]}

Mallon, E. ^{[3
]}

Doughty, J. ^{[4
]}

Pyne, S. ^{[2
]}

Pyne, N. J. ^{[2
]}

Edwards, J. ^{[1
]}

机构：

[1] Univ Glasgow, Inst Canc, Unit Expt Therapeut, Glasgow G11 6NT, Lanark, Scotland

[2] Univ Strathclyde, SIPBS, Cell Biol Grp, Glasgow G4 0RE, Lanark, Scotland

[3] Glasgow Western Infirm, Dept Pathol, Glasgow G11 6NT, Lanark, Scotland

[4] Glasgow Western Infirm, Dept Surg, Glasgow G11 6NT, Lanark, Scotland

来源：

BRITISH JOURNAL OF CANCER | 2012年 / 106卷 / 08期

关键词：

sphingosine; 1-phosphate; sphingosine kinase; oestrogen receptor; HER2; sphingosine 1-phosphate receptor 4; extracellular signal regulated kinase; SIGNAL-REGULATED KINASE-1/2; PROTEASOMAL-DEGRADATION; MAMMALIAN-CELLS; POOR SURVIVAL; G-PROTEIN; GROWTH; SPHINGOSINE-1-PHOSPHATE; FTY720;

D O I：

10.1038/bjc.2012.98

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

BACKGROUND: We previously reported that sphingosine 1-phosphate receptor 4 (S1P(4)) is expressed and stimulates the ERK-1/2 pathway via a human epidermal growth factor receptor 2 (HER2)-dependent mechanism in oestrogen receptor-negative (ER-) MDA-MB-453 breast cancer cells. METHODS: Clinical relevance of S1P(4) and sphingosine kinase 1 (SK1, which catalyses the formation of S1P) was assessed in a cohort of 140 ER- breast tumours by immunohistochemistry (IHC) and the weighted histoscore method. Additional evidence for a functional interaction between S1P(4) and SK1 and between HER2 and SK1 was obtained using MDA-MB-453 cells. RESULTS: High S1P(4) expression is associated with shorter disease-free (P = 0.014) and disease-specific survival (P = 0.004), and was independent on multivariate analysis. In addition, patients with tumours that contain high and low levels of SK1 and S1P(4), respectively, have a significantly shorter disease-free survival (P = 0.043) and disease-specific survival (P = 0.033) compared with patients whose tumours contain both low S1P(4) and SK1 levels. In addition, high tumour expression of SK1 was significantly associated with shorter disease-specific survival (P = 0.0001) in patients with HER2-positive tumours. Treatment of MDA-MB-453 cells with the SK1 inhibitor, SKi (2-(p-hydroxyanilino)-4-(p-chlorophenyl) thiazole) reduced the basal and S1P/S1P(4)-induced activation of ERK-1/2 and altered HER2 trafficking in these cells. CONCLUSION: These findings highlight an important role for S1P(4) and SK1 in ER- breast cancer progression. British Journal of Cancer (2012) 106, 1453-1459. doi: 10.1038/bjc.2012.98 www.bjcancer.com Published online 29 March 2012 (C) 2012 Cancer Research UK

引用

页码：1453 / 1459

页数：7

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