Document Type : Original Research


1 Dept. of Biology, Science Faculty, Shahid Beheshti University, Tehran, Iran

2 Pathology and Stem Cell Research Center, Pathology Department, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran

3 Dept. of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

4 Surgery Department, Kerman University of Medical Sciences, Kerman, Iran


Background & objective: Breast cancer is the leading cause of cancer related death in females. Sphingosine kinase 1 (SPHK1) and its product sphingosine-1-phosphate (S1P) are the essential key regulator molecules in breast cancer through their ability to promote cell proliferation, angiogenesis, cell proliferation, and lymphagiogenesis. SPHK1 is overexpressed in multiple types of cancer including breast cancer and is associated with resistance to treatment. The current study aimed at investigating the expression of SPHK1 in estrogen and progesterone receptors (ER, PR) negative in comparison to ER, and PR positive breast cancer and their normal controls, and also finding the relationship between SPHK1 expression and high body index (BMI) in the selected groups with breast cancer.
Methods: A total of 120 human breast cancer tissue specimens were analyzed for SPHK1 expression using quantitative real–time polymerase chain reaction (q RT-PCR) assay. Detection of hormonal status of breast cancer tissue samples was conducted by immunohistochemical assay.
Result: The current study findings showed that the level of SPHK1expression in the breast cancer tissue was significantly higher in patients with estrogen and progesterone negative receptors, compared to the ones without them (P-value< 0.05). The obtained data confirmed that the obesity in patients with ER negative was higher than the ones with positive receptors (BMI> 25).
Conclusion: The current study showed that expression of SPHK1gene was higher in the patients with ER and PR negative breast cancer and high BMI, compared with other groups.


1. World Cancer Report. International Agency for research on Cancer. 2008Retrieved 2011-02-26.
2. Beckmann MW, Bani MR, Fasching PA, Strick R and Lux MP. Risk and risk assessment for breast cancer: molecular and clinical aspects. Maturitas 2007.20; 57(1): 56-60.
3.Mousavi SM, Montazeri A, Mohagheghi MA, Jarrahi AM, Harirchi I, Najafi M, Ebrahimi M. Breast cancer in Iran: an epidemiological review. Breast J 2007; 13(4):383-91.
4. Lal P, Tan LK, Chen B. Correlation of HER-2 status with estrogen and progesterone receptors and histologic features in 3,655 invasive breast carcinomas. Am J Clin Pathol 2005; 123(4): 541-6.
5. Blanco G, Holli K, Heikkinen M, Kallioniemi OP, Taskinen P. Prognostic factors in recurrent breast cancer: relationship to site of recurrence, disease- free interval, female sex steroid receptors, ploidy and histological malignancy grading. Br J Cancer 1990; 62(1): 142-6.
6. Marzec KA, Baxter R C, and. Martin JL. Targeting Insulin-Like Growth Factor Binding Protein-3 Signaling in Triple-Negative Breast Cancer. BoiMed Res Int 2015; 2015:638526.
7. Cuvillier O, Nava VE, Murthy SK, Edsall LC, Levade T, Milstien S, Spiegel S. Sphingosine generation, cytochrome c release, and activation of caspase-7 in doxorubicin-induced apoptosis of MCF7 breast adenocarcinoma cells. Cell Death Differ2001; 8(2):162-71.
8. Herr DR, Chun J. Effects of LPA and S1P on the nervous system and implications for their involvement in disease. Curr Drug Targets2007;8 (1):155-67.
9. Spiegel S, Milstien S. Sphingosine-1-phosphate: an enigmatic signaling lipid. Nat Rev Mol Cell Biol2003; 4(5):397-407.
10. Shida D, Takabe K, Kapitonov D, Milstien S, Spiegel S. Targeting SphK1 as a new strategy against cancer. Curr Drug Targets 2008 Aug; 9(8):662-73.
11. Maceyka MSpiegel S.Sphingolipid metabolites in inflammatory disease.Nature2014; 5;510(7503):58-67. 
12. Pyne NJPyneS.Sphingosine 1-phosphate and cancer.Nat Rev Cancer 2010; 10(7):489-503. 
13. Alshaker H, Sauer L, Monteil D, Ottavini S, Strivats S, Bohler T, Pchejetshki D. Therapeutic potential of targeting SK1 in human cancers.Adv Cancer Res 2013; 117:143-200.
14. Zheng XD, Zhang Y, Qi XW, Wang MH, Sun P, Zhang Y, et al. Role of Sphk1 in the malignant transformation of breast epithelial cells and breast cancer progression. Indian J Cancer 2014 Oct-Dec; 51(4):524-9.
15. XiaP,GambleJR,WangL,PitsonSM,MorettiPA,WattenbergBW,D'AndreaRJ,Vadas MA et al. An oncogenic role of sphingosine kinase.CurrBiol2000; 10(23):1527-30.
16. Ko P, Kim D, You E, Jung J, Oh S, Kim J et al. Extracellular Matrix Rigidity-dependent Sphingosine-1-phosphate Secretion Regulates Metastatic Cancer Cell Invasion and Adhesion. Sci Rep 2016 Feb 15; 6:21564.
17. Tian H, Yu Z. Resveratrol induces apoptosis of leukemia cell line K562 by modulation of sphingosine kinase-1 pathway. Int J Clin Exp Phathol 2015 Mar 1; 8(3):2755-62.
18. Salama MF, Carroll B, Adada M, PuLkoski-Gross M, Hannun YA, Obeid LM. A novel role of sphingosine kinase-1 in the invasion and angiogenesis of VHL mutant clear cell renal cell carcinoma. FASEB J 2015 Jul; 29(7):2803-13.
19. Beach JA, Aspuria PJ, Cheon DJ, Lawenson K, Agadjanian H, Walsh CS. Sphingosine kinase 1 is required for TGF-β mediated fibroblastto- myofibroblast differentiation in ovarian cancer. Oncotarget 2016 Jan 26; 7(4):4167-82.
20. Le ScolanE ,Pchejetski D,BannoY, DenisN, MayeuxP, Vainchenker W et al. Overexpression of sphingosine kinase 1 is an oncogenic event in erythroleukemic progression. Blood 2005;106(5):1808-16.
21. Zhao R, Milstien S, Zhou H, Spiegel S, Takabe K: Sphingosine-1-phosphateproduced by sphingosine kinase 1 promotes breast cancer progressionby stimulating angiogenesis and lymphangiogenesis. Cancer Res 2012 Feb 1; 72(3):726–735.
22. Wang E, NgalameY Panelli MC, Nguyen-Jackson H, Deavers M, Mueller P, HuW, Savary CA et al. Peritoneal and subperitoneal stroma may facilitate regional spread of ovarian cancer. Clin Cancer Res 2005; 11(1):113-22.
23. Butcher DT, Alliston T, Weaver VM. A tense situation: forcing tumour progression.Net Rev Cancer 2009 Feb; 9(2):108-22.
24. Leventl KR, Yu H, Kass L, Lakins JN, Egeblad M, ErlerJT, Fong SF et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. cell 2009 Nov 25;139(5):891-906..
25. Shirai K, Kaneshiro T, Wada M, Furuya H, Bielawski J, Hannun YA, Obeid LM, et al. A role of sphingosine kinase 1 in head & neck carcinogenesis. Cancer Prev Res (Phila). 2011 Mar; 4(3):454-62.
26. Tsuchida J, Nagahashi M, Nakajima M, Moro K, Tatsuda K, Ramanathan R. Breast cancer sphingosine-1-phosphate is associated with phospho-sphingosine kinase 1 and lymphatic metastasis.JSurgRes2016; 205(1):85-94.
27. Ruckhäberle E, Rody A, Engels K, Gaetje R, vonMinckwitz G, Schiffmann S et al. Microarray analysis of altered sphingolipid metabolism reveals prognostic significance of sphingosine kinase 1 in breast cancer. Breast Cancer Res Treat  2008; 112(1):41-52.
28. Long JS, Edwards J, Watson C, Tovey S, Mair KM, Schiff R et al. Sphingosine kinase 1 induces tolerance to human epidermal growth factor receptor 2 and prevents formation of a migratory phenotype in response to sphingosine 1-phosphate in estrogen receptor-positive breast cancer cells. Mol Cell Biol 2010 Aug; 30(15):3827-41.
29. Pyne NJ, Tonelli F, Lim KG, Long J, Edwards J, Pyne S: Targeting sphingosine kinase 1 in cancer. AdvBiolRegul 2012 Jan; 52:31–38.
30. Ohotski J, Long JS, Orange C, Elsberger B, Mallon E, Doughty J.Expression of sphingosine 1-phosphate receptor4 and sphingosine kinase 1 is associated with outcome in oestrogen receptor-negative breast cancer. Br J Cancer 2012; Apr 10; 106(8):1453-9.
31. French KJ,SchrecengostRS,LeeBD,ZhuangY,SmithSN,EberlyJL,YunJK,SmithCD.Discovery and evaluation of inhibitors of human sphingosine kinase.CancerRes2003; 63(18):5962-9.
32. Alshker H, Krell J, Frampton AE, Waxman J, BlyussO,Zaikin A. et al. Leptin induces upregulation of sphingosine kinase 1 in oestrogen receptor-negative breast cancer via Src family kinase-mediated, janus kinase 2-independent pathway. Breast Cancer Res 2014 Oct 25; 16(5):426.
33. Błachnio-ZabielskaAU,PułkaM,BaranowskiM,NikołajukA,ZabielskiP,Górska al.Ceramidemetabolismisaffectedbyobesityanddiabetesinhumanadipose tissue.J Cell Physiol2012; 227(2):550-7.
34. Ruckhaberle E, Rody A, Engels K, Gaetje R, von Minckwitz G, Schiffmann S, Grosch S et al. Microarray analysis of altered sphingolipid metabolism reveals prognostic significance ofsphingosine kinase 1 in breast cancer. Breast Cancer Res Treat 2008 Nov; 112(1):41–52.
35. Blachnio-Zabielska AU, Pulka M, Baranowski M, Nikolajuk A, ZabielskiP,Gorska M. Ceramide metabolism is affected by obesity and diabetes in human adipose tissue. J Cell Physiol 2012 Feb; 227(2):550-7.
36. Miyoshi Y,FunahashiT, TanakaS, TaguchiT, TamakiY, Shimomura I et al High expression of leptin receptor mRNA in breast cancer tissue predicts poor prognosis for patients with high, but not low, serum leptin levels. Int J Cancer 2006; 118(6):1414-9.
37. MacciòA, MadedduC, GramignanoG, MulasC, FlorisC, Massa D et al. Correlation of body mass index and leptin with tumor size and stage of disease inhormone-dependent postmenopausal breast cancer preliminary results and the rapeuticimplications. JMol Med (Berl)  2010; 88(7):677-86.
38. Ishikawa M,Kitayama J, Nagawa H. Enhanced expression of leptin and leptin receptor (OB-R) in human breast cancer. Clin Cancer Res 2004; 10(13):4325-31.
39. Visentin B, Vekich JA, Sibbald BJ, Cavalli AL, Moreno KM, Matteo RG et al. Validation of an anti-sphingosine-1-phosphate antibody as a potential therapeutic in reducing growth, invasion, and angiogenesis in multiple tumor lineages. Cancer Cell 2006 ;9(3):225-38.
40. Nagahashi M, Ramachandran S, Kim EY, Alle good JC, Rashid OM, Yamada A et al.Sphingosine-1-phosphate produced by sphingosine kinase 1 promotes breast cancer progression by stimulating angiogenesis and lymphangiogenesis.CancerRes2012; 72(3):726-35.
41. Mukhopadhyay P, Ramanathan R, Takabe K.S1P promotes breast cancer progression by angiogenesis and lymphangiogenesis. Breast Cancer Manag2015; 4(5):241-244.
 42. Sobue S, Lwasiki T, Suqisaki C, Nagatu K, Kikuchi R, Murakami M. QuantitativeRT-PCRanalysis of sphingolipid metabolic enzymes in acuteleukemia and myelodysplastic syndromes. Leukemia 2006 Nov; 20(11):2042-6.
43. Johnson KR, Johnson KY, Crellin HG, Ogretmen B, Boylan AM, Harley RA, et al. Immunohistochemical distribution of sphingosine kinase 1 in normal and tumor lung tissue. J Histochem Cytochem 2005 Sep; 53(9):1159-66.
44. TahaTA,KitataniK,El-Alwani M, Bielawski J, Hannun YA, Obeid LM. Loss of sphingosine kinase-1 activates the intrinsic pathway of programmed cell death: modulation of sphingolipid levels and the induction of apoptosis.FASEBJ2006; 20(3):482-4.