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Oncostatin-M promotes phenotypic changes associated with mesenchymal and stem cell-like differentiation in breast cancer

Oncogene volume 33, pages 1485–1494 (2014)Cite this article

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Abstract

Cancer stem cell (CSC) biology and the epithelial-to-mesenchymal transition (EMT) are thought to be mechanistically linked and may be key components of cancer development and progression. However, stimuli that induce EMT and CSC-like features (‘stemness’) are poorly defined. We and others have shown that the inflammatory cytokine oncostatin-M (OSM) mediates phenotypic changes in breast cancer that are consistent with EMT and dedifferentiation, including enhanced migration and loss of hormone receptors. In this study, we have expanded on these prior observations to determine whether OSM is a cell-extrinsic driver of EMT and/or stemness. OSM stimulation of the luminal breast cancer cell lines MCF7 and T47D induced EMT features including loss of membranous E-cadherin and induction of snail and slug expression. OSM treatment markedly enhanced the formation of mammospheres (up to 20-fold, P<0.001), which displayed high expression of the pluripotency factor SOX2. The proportion of cells with a CD44highCD24−/low phenotype was similarly increased by OSM (P<0.001). OSM-induced mammosphere formation and CD44highCD24−/low induction was dependent on PI3K signalling. In silico analysis of human breast tumours (from a publicly available data set, n=322) confirmed that co-expression of a PI3K transcriptional signature, but not MAPK or STAT3 signatures, was necessary to detect an association between OSMR and poor prognosis. Assessment of a second in silico data set (n=241 breast tumours) confirmed a significant relationship between OSMR, markers of EMT and CSCs, and chemotherapy resistance. Direct analysis of mRNA expression by RT–PCR in a third cohort (n=72 breast tumours) demonstrated that high expression of OSM is associated positively with indicators of EMT (SNAI1, P<0.001) and stemness (SOX2, P<0.05). Our data suggest for the first time that OSM may promote a clinically relevant EMT/CSC-like phenotype in human breast cancer via a PI3K-dependent mechanism.

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References

  1. May CD, Sphyris N, Evans KW, Werden SJ, Guo W, Mani SA . Epithelial-mesenchymal transition and cancer stem cells: a dangerously dynamic duo in breast cancer progression. Breast Cancer Res 2011; 13: 202.

    Article  Google Scholar 

  2. Lawson JC, Blatch GL, Edkins AL . Cancer stem cells in breast cancer and metastasis. Breast Cancer Res Treat 2009; 118: 241–254.

    Article  Google Scholar 

  3. Klymkowsky MW, Savagner P . Epithelial-mesenchymal transition: a cancer researcher's conceptual friend and foe. Am J Pathol 2009; 174: 1588–1593.

    Article  CAS  Google Scholar 

  4. Korkaya H, Liu S, Wicha MS . Breast cancer stem cells, cytokine networks, and the tumor microenvironment. J Clin Invest 2011; 121: 3804–3809.

    Article  CAS  Google Scholar 

  5. West NR, Watson PH . S100A7 (psoriasin) is induced by the proinflammatory cytokines oncostatin-M and interleukin-6 in human breast cancer. Oncogene 2010; 29: 2083–2092.

    Article  CAS  Google Scholar 

  6. Holzer RG, Ryan RE, Tommack M, Schlekeway E, Jorcyk CL . Oncostatin M stimulates the detachment of a reservoir of invasive mammary carcinoma cells: role of cyclooxygenase-2. Clin Exp Metastasis 2004; 21: 167–176.

    Article  CAS  Google Scholar 

  7. Jorcyk CL, Holzer RG, Ryan RE . Oncostatin M induces cell detachment and enhances the metastatic capacity of T-47D human breast carcinoma cells. Cytokine 2006; 33: 323–336.

    Article  CAS  Google Scholar 

  8. Zhang F, Li C, Halfter H, Liu J . Delineating an oncostatin M-activated STAT3 signaling pathway that coordinates the expression of genes involved in cell cycle regulation and extracellular matrix deposition of MCF-7 cells. Oncogene 2003; 22: 894–905.

    Article  CAS  Google Scholar 

  9. West NR, Murphy LC, Watson PH . Oncostatin-M suppresses estrogen receptor-alpha expression and is associated with poor outcome in human breast cancer. Endocr Relat Cancer 2012; 19: 181–195.

    Article  CAS  Google Scholar 

  10. Rakha EA, El-Sayed ME, Reis-Filho JS, Ellis IO . Expression profiling technology: its contribution to our understanding of breast cancer. Histopathology 2008; 52: 67–81.

    Article  CAS  Google Scholar 

  11. Prat A, Parker JS, Karginova O, Fan C, Livasy C, Herschkowitz JI et al. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res 2010; 12: R68.

    Article  Google Scholar 

  12. Fulford LG, Easton DF, Reis-Filho JS, Sofronis A, Gillett CE, Lakhani SR et al. Specific morphological features predictive for the basal phenotype in grade 3 invasive ductal carcinoma of breast. Histopathology 2006; 49: 22–34.

    Article  CAS  Google Scholar 

  13. Chavey C, Bibeau F, Gourgou-Bourgade S, Burlinchon S, Boissiere F, Laune D et al. Oestrogen receptor negative breast cancers exhibit high cytokine content. Breast Cancer Res 2007; 9: R15.

    Article  Google Scholar 

  14. Teschendorff AE, Journee M, Absil PA, Sepulchre R, Caldas C . Elucidating the altered transcriptional programs in breast cancer using independent component analysis. PLoS Comput Biol 2007; 3: e161.

    Article  Google Scholar 

  15. Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G, Schaper F . Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 2003; 374 (Pt 1): 1–20.

    Article  CAS  Google Scholar 

  16. Tanaka M, Miyajima A . Oncostatin M, a multifunctional cytokine. Rev Physiol Biochem Pharmacol 2003; 149: 39–52.

    Article  CAS  Google Scholar 

  17. de Herreros AG, Peiro S, Nassour M, Savagner P . Snail family regulation and epithelial mesenchymal transitions in breast cancer progression. J Mammary Gland Biol Neoplasia 2010; 15: 135–147.

    Article  Google Scholar 

  18. Dhasarathy A, Kajita M, Wade PA . The transcription factor snail mediates epithelial to mesenchymal transitions by repression of estrogen receptor-alpha. Mol Endocrinol 2007; 21: 2907–2918.

    Article  CAS  Google Scholar 

  19. Ye Y, Xiao Y, Wang W, Yearsley K, Gao JX, Shetuni B et al. ERalpha signaling through slug regulates E-cadherin and EMT. Oncogene 2010; 29: 1451–1462.

    Article  CAS  Google Scholar 

  20. Plath K, Lowry WE . Progress in understanding reprogramming to the induced pluripotent state. Nat Rev Genet 2011; 12: 253–265.

    Article  CAS  Google Scholar 

  21. Dontu G, Abdallah WM, Foley JM, Jackson KW, Clarke MF, Kawamura MJ et al. In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev 2003; 17: 1253–1270.

    Article  CAS  Google Scholar 

  22. Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C et al. let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 2007; 131: 1109–1123.

    Article  CAS  Google Scholar 

  23. Ponti D, Costa A, Zaffaroni N, Pratesi G, Petrangolini G, Coradini D et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res 2005; 65: 5506–5511.

    Article  CAS  Google Scholar 

  24. Leis O, Eguiara A, Lopez-Arribillaga E, Alberdi MJ, Hernandez-Garcia S, Elorriaga K et al. Sox2 expression in breast tumours and activation in breast cancer stem cells. Oncogene 2011; 31: 1354–1365.

    Article  Google Scholar 

  25. Takahashi K, Yamanaka S . Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126: 663–676.

    Article  CAS  Google Scholar 

  26. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF . Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003; 100: 3983–3988.

    Article  CAS  Google Scholar 

  27. Creighton CJ, Fu X, Hennessy BT, Casa AJ, Zhang Y, Gonzalez-Angulo AM et al. Proteomic and transcriptomic profiling reveals a link between the PI3K pathway and lower estrogen-receptor (ER) levels and activity in ER+ breast cancer. Breast Cancer Res 2010; 12: R40.

    Article  Google Scholar 

  28. Loboda A, Nebozhyn M, Klinghoffer R, Frazier J, Chastain M, Arthur W et al. A gene expression signature of RAS pathway dependence predicts response to PI3K and RAS pathway inhibitors and expands the population of RAS pathway activated tumors. BMC Med Genomics 2010; 3: 26.

    Article  Google Scholar 

  29. Alvarez JV, Febbo PG, Ramaswamy S, Loda M, Richardson A, Frank DA . Identification of a genetic signature of activated signal transducer and activator of transcription 3 in human tumors. Cancer Res 2005; 65: 5054–5062.

    Article  CAS  Google Scholar 

  30. Popovici V, Chen W, Gallas BG, Hatzis C, Shi W, Samuelson FW et al. Effect of training-sample size and classification difficulty on the accuracy of genomic predictors. Breast Cancer Res 2010; 12: R5.

    Article  Google Scholar 

  31. Colleoni M, Bagnardi V, Rotmensz N, Gelber RD, Viale G, Pruneri G et al. Increasing steroid hormone receptors expression defines breast cancer subtypes non responsive to preoperative chemotherapy. Breast Cancer Res Treat 2009; 116: 359–369.

    Article  CAS  Google Scholar 

  32. Colleoni M, Viale G, Zahrieh D, Pruneri G, Gentilini O, Veronesi P et al. Chemotherapy is more effective in patients with breast cancer not expressing steroid hormone receptors: a study of preoperative treatment. Clin Cancer Res 2004; 10: 6622–6628.

    Article  CAS  Google Scholar 

  33. Guarneri V, Broglio K, Kau SW, Cristofanilli M, Buzdar AU, Valero V et al. Prognostic value of pathologic complete response after primary chemotherapy in relation to hormone receptor status and other factors. J Clin Oncol 2006; 24: 1037–1044.

    Article  Google Scholar 

  34. Ring AE, Smith IE, Ashley S, Fulford LG, Lakhani SR . Oestrogen receptor status, pathological complete response and prognosis in patients receiving neoadjuvant chemotherapy for early breast cancer. Br J Cancer 2004; 91: 2012–2017.

    Article  CAS  Google Scholar 

  35. Zeisberg M, Neilson EG . Biomarkers for epithelial-mesenchymal transitions. J Clin Invest 2009; 119: 1429–1437.

    Article  CAS  Google Scholar 

  36. Christiansen JJ, Rajasekaran AK . Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. Cancer Res 2006; 66: 8319–8326.

    Article  CAS  Google Scholar 

  37. Mego M, Mani SA, Cristofanilli M . Molecular mechanisms of metastasis in breast cancer—clinical applications. Nat Rev Clin Oncol 2010; 7: 693–701.

    Article  CAS  Google Scholar 

  38. Balic M, Lin H, Young L, Hawes D, Giuliano A, McNamara G et al. Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clin Cancer Res 2006; 12: 5615–5621.

    Article  CAS  Google Scholar 

  39. Polyak K, Weinberg RA . Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 2009; 9: 265–273.

    Article  CAS  Google Scholar 

  40. Dubois-Marshall S, Thomas JS, Faratian D, Harrison DJ, Katz E . Two possible mechanisms of epithelial to mesenchymal transition in invasive ductal breast cancer. Clin Exp Metastasis 2011; 28: 811–818.

    Article  CAS  Google Scholar 

  41. Liu J, Spence MJ, Wallace PM, Forcier K, Hellstrom I, Vestal RE . Oncostatin M-specific receptor mediates inhibition of breast cancer cell growth and down-regulation of the c-myc proto-oncogene. Cell Growth Differ 1997; 8: 667–676.

    CAS  PubMed  Google Scholar 

  42. Grant SL, Hammacher A, Douglas AM, Goss GA, Mansfield RK, Heath JK et al. An unexpected biochemical and functional interaction between gp130 and the EGF receptor family in breast cancer cells. Oncogene 2002; 21: 460–474.

    Article  CAS  Google Scholar 

  43. Douglas AM, Goss GA, Sutherland RL, Hilton DJ, Berndt MC, Nicola NA et al. Expression and function of members of the cytokine receptor superfamily on breast cancer cells. Oncogene 1997; 14: 661–669.

    Article  CAS  Google Scholar 

  44. Rodriguez-Pinilla SM, Sarrio D, Moreno-Bueno G, Rodriguez-Gil Y, Martinez MA, Hernandez L et al. Sox2: a possible driver of the basal-like phenotype in sporadic breast cancer. Mod Pathol 2007; 20: 474–481.

    Article  CAS  Google Scholar 

  45. Emberley ED, Murphy LC, Watson PH . S100A7 and the progression of breast cancer. Breast Cancer Res 2004; 6: 153–159.

    Article  CAS  Google Scholar 

  46. Emberley ED, Niu Y, Curtis L, Troup S, Mandal SK, Myers JN et al. The S100A7-c-Jun activation domain binding protein 1 pathway enhances prosurvival pathways in breast cancer. Cancer Res 2005; 65: 5696–5702.

    Article  CAS  Google Scholar 

  47. Clarkson RW, Boland MP, Kritikou EA, Lee JM, Freeman TC, Tiffen PG et al. The genes induced by signal transducer and activators of transcription (STAT)3 and STAT5 in mammary epithelial cells define the roles of these STATs in mammary development. Mol Endocrinol 2006; 20: 675–685.

    Article  CAS  Google Scholar 

  48. Guo L, Chen C, Shi M, Wang F, Chen X, Diao D et al. Stat3-coordinated Lin-28–let-7–HMGA2 and miR-200–ZEB1 circuits initiate and maintain oncostatin M-driven epithelial–mesenchymal transition. Oncogene 2013; 32: 5272–5282.

    Article  CAS  Google Scholar 

  49. Dangi-Garimella S, Yun J, Eves EM, Newman M, Erkeland SJ, Hammond SM et al. Raf kinase inhibitory protein suppresses a metastasis signalling cascade involving LIN28 and let-7. EMBO J 2009; 28: 347–358.

    Article  CAS  Google Scholar 

  50. Zhou J, Wulfkuhle J, Zhang H, Gu P, Yang Y, Deng J et al. Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance. Proc Natl Acad Sci USA 2007; 104: 16158–16163.

    Article  CAS  Google Scholar 

  51. Korkaya H, Paulson A, Charafe-Jauffret E, Ginestier C, Brown M, Dutcher J et al. Regulation of mammary stem/progenitor cells by PTEN/Akt/beta-catenin signaling. PLoS Biol 2009; 7: e1000121.

    Article  Google Scholar 

  52. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008; 133: 704–715.

    Article  CAS  Google Scholar 

  53. Morel AP, Lievre M, Thomas C, Hinkal G, Ansieau S, Puisieux A . Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS One 2008; 3: e2888.

    Article  Google Scholar 

  54. Asiedu MK, Ingle JN, Behrens MD, Radisky DC, Knutson KL . TGFbeta/TNF(alpha)-mediated epithelial-mesenchymal transition generates breast cancer stem cells with a claudin-low phenotype. Cancer Res 2011; 71: 4707–4719.

    Article  CAS  Google Scholar 

  55. Bhat-Nakshatri P, Campbell RA, Patel NM, Newton TR, King AJ, Marshall MS et al. Tumour necrosis factor and PI3-kinase control oestrogen receptor alpha protein level and its transrepression function. Br J Cancer 2004; 90: 853–859.

    Article  CAS  Google Scholar 

  56. Iliopoulos D, Hirsch HA, Wang G, Struhl K . Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion. Proc Natl Acad Sci USA 2011; 108: 1397–1402.

    Article  CAS  Google Scholar 

  57. Sansone P, Storci G, Tavolari S, Guarnieri T, Giovannini C, Taffurelli M et al. IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. J Clin Invest 2007; 117: 3988–4002.

    Article  CAS  Google Scholar 

  58. Sullivan NJ, Sasser AK, Axel AE, Vesuna F, Raman V, Ramirez N et al. Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells. Oncogene 2009; 28: 2940–2947.

    Article  CAS  Google Scholar 

  59. Ginestier C, Liu S, Diebel ME, Korkaya H, Luo M, Brown M et al. CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. J Clin Invest 2010; 120: 485–497.

    Article  CAS  Google Scholar 

  60. Hardt O, Wild S, Oerlecke I, Hofmann K, Luo S, Wiencek Y et al. Highly sensitive profiling of CD44(+)/CD24(-) breast cancer stem cells by combining global mRNA amplification and next generation sequencing: Evidence for a hyperactive PI3K pathway. Cancer Lett 2012; 325: 165–174.

    Article  CAS  Google Scholar 

  61. Blanchard F, Wang Y, Kinzie E, Duplomb L, Godard A, Baumann H . Oncostatin M regulates the synthesis and turnover of gp130, leukemia inhibitory factor receptor alpha, and oncostatin M receptor beta by distinct mechanisms. J Biol Chem 2001; 276: 47038–47045.

    Article  CAS  Google Scholar 

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Acknowledgements

We are grateful to members of the Deeley Research Centre for helpful discussion. We thank the Manitoba Breast Tumour Bank (a member of the Canadian Tumour Repository Network) for providing breast cancer tissue specimens and the authors of the UNC and MAQC cohorts for making their data freely available. Financial support was from the Canadian Breast Cancer Foundation (CBCF), BC/Yukon chapter and the BC Cancer Foundation. NRW was supported by a US DOD Breast Cancer Research Program Predoctoral award (W81XWH-08-1-0781). JIM is supported by a CBCF BC/Yukon Region postdoctoral fellowship.

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  1. Deeley Research Centre, British Columbia Cancer Agency, Victoria, British Columbia, Canada

    N R West, J I Murray & P H Watson

  2. Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada

    N R West & P H Watson

  3. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada

    P H Watson

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West, N., Murray, J. & Watson, P. Oncostatin-M promotes phenotypic changes associated with mesenchymal and stem cell-like differentiation in breast cancer. Oncogene 33, 1485–1494 (2014). https://doi.org/10.1038/onc.2013.105

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