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Evaluating the antitumor activity of sphingosine-1-phosphate against human triple-negative breast cancer cells with basal-like morphology

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Summary

Sphingosine-1-phosphate (S1P) is an important sphingolipid metabolite that regulates a wide range of physiological and pathophysiological processes. Our previous studies show that S1P selectively induces cell apoptosis in human breast cancer luminal A subtype cell line MCF7. In addition, S1P exhibits synergistic effects with chemotherapy drugs against both MCF7 and luminal B subtype cell line MDA-MB-361 at concentration in the high nM to low μM range. In the current study, we evaluated the effect of S1P on proliferation, apoptosis and cytotoxicity towards a panel of nine triple-negative breast cancer with basal-like morphology (TNBC-BL) cell lines (HCC1599, HCC1937, HCC1143, MDA-MB-468, HCC38, HCC70, HCC1806, HCC1187 and DU4475) in the same concentration range. S1P exhibited mild to moderate effects (<20% increase comparted to control) towards the TNBC-BL cell lines except HCC38, HCC70 and HCC1806. Furthermore, it increased cell apoptosis by ~15–20% in all the cell lines compared to the control, and elicited moderate to strong cytotoxic effect towards all cell lines except MDA-MB-468 and HCC1806. However, no synergistic/additive effect was observed between S1P and chemotherapy drug docetaxel for any TNBC-BL cell line.

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References

  1. 1.

    Haffty BG, Yang Q, Reiss M, Kearney T, Higgins SA, Weidhaas J, Harris L, Hait W, Toppmeyer D (2006) Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer. J Clin Oncol 24(36):5652–5657

  2. 2.

    Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, Lickley LA, Rawlinson E, Sun P, Narod SA (2007) Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 13(15 Pt 1):4429–4434

  3. 3.

    Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F, Ollila DW, Sartor CI, Graham ML, Perou CM (2007) The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res 13(8):2329–2334

  4. 4.

    Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, Pietenpol JA (2011) Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 121(7):2750–2767

  5. 5.

    Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, Hernandez-Boussard T, Livasy C, Cowan D, Dressler L, Akslen LA, Ragaz J, Gown AM, Gilks CB, van de Rijn M, Perou CM (2004) Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 10(16):5367–5374

  6. 6.

    Abd El-Rehim DM, Pinder SE, Paish CE, Bell J, Blamey RW, Robertson JF, Nicholson RI, Ellis IO (2004) Expression of luminal and basal cytokeratins in human breast carcinoma. J Pathol 203(2):661–671

  7. 7.

    Livasy CA, Karaca G, Nanda R, Tretiakova MS, Olopade OI, Moore DT, Perou CM (2006) Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. Mod Pathol 19(2):264–271

  8. 8.

    Eroles P, Bosch A, Pérez-Fidalgo JA, Lluch A (2012) Molecular biology in breast cancer: intrinsic subtypes and signaling pathways. Cancer Treat Rev 38(6):698–707

  9. 9.

    Kumar P, Aggarwal R (2016) An overview of triple-negative breast cancer. Arch Gynecol Obstet 293(2):247–269

  10. 10.

    Bertucci F, Finetti P, Birnbaum D (2012) Basal breast cancer: a complex and deadly molecular subtype. Curr Mol Med 12(1):96–110

  11. 11.

    Dietze EC, Sistrunk C, Miranda-Carboni G, O'Regan R, Seewaldt VL (2015) Triple-negative breast cancer in African-American women: disparities versus biology. Nat Rev Cancer 15(4):248–254

  12. 12.

    Siddharth S, Sharma D (2018) Racial disparity and triple-negative breast cancer in African-American women: a multifaceted affair between obesity, biology, and socioeconomic determinants. Cancers (Basel) 10(12):514

  13. 13.

    Pyne NJ, Pyne S (2010) Sphingosine 1-phosphate and cancer. Nat Rev Cancer 10(7):489–503

  14. 14.

    Strub GM, Maceyka M, Hait NC, Milstien S, Spiegel S (2010) Extracellular and intracellular actions of sphingosine-1-phosphate. Adv Exp Med Biol 688:141–155

  15. 15.

    Pulkoski-Gross MJ, Obeid LM (2018) Molecular mechanisms of regulation of sphingosine kinase 1. Biochim Biophys Acta Mol Cell Biol Lipids 1863(11):1413–1422

  16. 16.

    Takabe K, Paugh SW, Milstien S, Spiegel S (2008) “Inside-out” signaling of sphingosine-1-phosphate: therapeutic targets. Pharmacol Rev 60(2):181–195

  17. 17.

    Pyne NJ, Tonelli F, Lim KG, Long JS, Edwards J, Pyne S (2012) Sphingosine 1-phosphate signalling in cancer. Biochem Soc Trans 40(1):94–100

  18. 18.

    Deng J, Liu Y, Lee H, Herrmann A, Zhang W, Zhang C, Shen S, Priceman SJ, Kujawski M, Pal SK, Raubitschek A, Hoon DS, Forman S, Figlin RA, Liu J, Jove R, Yu H (2012) S1PR1-STAT3 signaling is crucial for myeloid cell colonization at future metastatic sites. Cancer Cell 21(5):642–654

  19. 19.

    Hirata N, Yamada S, Shoda T, Kurihara M, Sekino Y, Kanda Y (2014) Sphingosine-1-phosphate promotes expansion of cancer stem cells via S1PR3 by a ligand-independent Notch activation. Nat Commun 5:4806

  20. 20.

    Liu S, Ni C, Zhang D, Sun H, Dong X, Che N, Liang X, Chen C, Liu F, Bai J, Lin X, Zhao X, Sun B (2019) S1PR1 regulates the switch of two angiogenic modes by VE-cadherin phosphorylation in breast cancer. Cell Death Dis 10(3):200

  21. 21.

    Adada M, Canals D, Hannun YA, Obeid LM (2013) Sphingosine-1-phosphate receptor 2. FEBS J 280(24):6354–6366

  22. 22.

    Flori M, Schmid CA, Sumrall ET, Tzankov A, Law CW, Robinson MD, Müller A (2016) The hematopoietic oncoprotein FOXP1 promotes tumor cell survival in diffuse large B-cell lymphoma by repressing S1PR2 signaling. Blood 127(11):1438–1448

  23. 23.

    Olesch C, Ringel C, Brüne B, Weigert A (2017) Beyond immune cell migration: the emerging role of the sphingosine-1-phosphate receptor S1PR4 as a modulator of innate immune cell activation. Mediat Inflamm 2017:6059203

  24. 24.

    Drouillard A, Mathieu AL, Marçais A, Belot A, Viel S, Mingueneau M, Guckian K, Walzer T (2018) S1PR5 is essential for human natural killer cell migration toward sphingosine-1 phosphate. J Allergy Clin Immunol 141(6):2265–2268.e1

  25. 25.

    Okada T, Ding G, Sonoda H, Kajimoto T, Haga Y, Khosrowbeygi A, Gao S, Miwa N, Jahangeer S, Nakamura S (2005) Involvement of N-terminal-extended form of sphingosine kinase 2 in serum-dependent regulation of cell proliferation and apoptosis. J Biol Chem 280(43):36318–36325

  26. 26.

    Sankala HM, Hait NC, Paugh SW, Shida D, Lépine S, Elmore LW, Dent P, Milstien S, Spiegel S (2007) Involvement of sphingosine kinase 2 in p53-independent induction of p21 by the chemotherapeutic drug doxorubicin. Cancer Res 67(21):10466–10474

  27. 27.

    Hait NC, Allegood J, Maceyka M, Strub GM, Harikumar KB, Singh SK, Luo C, Marmorstein R, Kordula T, Milstien S, Spiegel S (2009) Regulation of histone acetylation in the nucleus by sphingosine-1-phosphate. Science 325(5945):1254–1257

  28. 28.

    Ling B, Chen L, Alcorn J, Ma B, Yang J (2011) Sphingosine-1-phosphate: a potential therapeutic agent against human breast cancer. Investig New Drugs 29(2):396–399

  29. 29.

    Sultan A, Ling B, Zhang H, Ma B, Michel D, Alcorn J, Yang J (2013) Synergistic effect between sphingosine-1-phosphate and chemotherapy drugs against human brain-metastasized breast cancer MDA-MB-361 cells. J Cancer 4(4):315–319

  30. 30.

    Chandrashekar DS, Bashel B, Balasubramanya SAH, Creighton CJ, Ponce-Rodriguez I, Chakravarthi BVSK, Varambally S (2017) UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia 19(8):649–658

  31. 31.

    Hale JJ, Lynch CL, Neway W, Mills SG, Hajdu R, Keohane CA, Rosenbach MJ, Milligan JA, Shei GJ, Parent SA, Chrebet G, Bergstrom J, Card D, Ferrer M, Hodder P, Strulovici B, Rosen H, Mandala S (2004) A rational utilization of high-throughput screening affords selective, orally bioavailable 1-benzyl-3-carboxyazetidine sphingosine-1-phosphate-1 receptor agonists. J Med Chem 47(27):6662–6665

  32. 32.

    Rosenberg AJ, Liu H, Tu Z (2015) A practical process for the preparation of [32P]S1P and binding assay for S1P receptor ligands. Appl Radiat Isot 102:5–9

  33. 33.

    Maiti A, Takabe K, Hait NC (2017) Metastatic triple-negative breast cancer is dependent on SphKs/S1P signaling for growth and survival. Cell Signal 32:85–92

  34. 34.

    Singh SK, Spiegel S (2019) Sphingosine-1-phosphate signaling: a novel target for simultaneous adjuvant treatment of triple negative breast cancer and chemotherapy-induced neuropathic pain. Adv Biol Regul 100670. https://doi.org/10.1016/j.jbior.2019.100670

  35. 35.

    Gude DR, Alvarez SE, Paugh SW, Mitra P, Yu J, Griffiths R, Barbour SE, Milstien S, Spiegel S (2008) Apoptosis induces expression of sphingosine kinase 1 to release sphingosine-1-phosphate as a “come-and-get-me” signal. FASEB J 22(8):2629–2638

  36. 36.

    Ader I, Gstalder C, Bouquerel P, Golzio M, Andrieu G, Zalvidea S, Richard S, Sabbadini RA, Malavaud B, Cuvillier O (2015) Neutralizing S1P inhibits intratumoral hypoxia, induces vascular remodelling and sensitizes to chemotherapy in prostate cancer. Oncotarget 6(15):13803–13821

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Acknowledgements

We would like to thank Dr. Jane Alcorn, College of Pharmacy and Nutrition, University of Saskatchewan, for her valuable suggestions.

Funding

The work was supported in part by a President’s NSERC grant from the University of Saskatchewan (Saskatoon, SK, Canada) and a research group grant from the Saskatchewan Health Research Foundation (Saskatoon, SK, Canada).

Author information

This research work was designed by Jian Yang and carried out by Omar Abuhussein.

Correspondence to Jian Yang.

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Omar Abuhussein declares that he has no conflict of interest. Jian Yang declares that he has no conflict of interest.

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Abuhussein, O., Yang, J. Evaluating the antitumor activity of sphingosine-1-phosphate against human triple-negative breast cancer cells with basal-like morphology. Invest New Drugs (2020). https://doi.org/10.1007/s10637-020-00909-2

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Keywords

  • Sphingosine-1-phosphate
  • Triple-negative breast cancer with basal-like morphology (TNBC-BL)
  • Cell proliferation
  • Cytotoxicity
  • Cell apoptosis
  • Combination therapy