Skip to main content

Advertisement

Log in

Two possible mechanisms of epithelial to mesenchymal transition in invasive ductal breast cancer

  • Research Paper
  • Published:
Clinical & Experimental Metastasis Aims and scope Submit manuscript

Abstract

Epithelial to mesenchymal transition (EMT) occurs in embryogenesis and normal development. It has been predominantly described in vitro and in animal studies, but EMT is also implicated in the progression of many cancers with proposed roles in invasion, metastasis and resistance to treatment. It is closely associated with loss of epithelial-specific protein expression and up-regulation of mesenchymal proteins, but several pathways are implicated in its execution. We explored what are the expression patterns of EMT proteins in human breast cancer. We interrogated two independent cohorts enriched for high-grade, invasive, ductal breast cancers. We used quantitative immunofluorescence to study the expression of key EMT proteins. Statistical associations to define protein profiles were based on Pearson’s correlations. E-cadherin down-regulation in breast cancer was associated with β-catenin down-regulation, but not with up-regulation of mesenchymal markers. While EMT-related transcription repressors were expressed in some breast cancers, their expression did not negatively correlate with E-cadherin. Instead, an additional EMT profile was identified, composing Snail and Slug. In conclusion, EMT occurs in human breast cancer in a manner distinct to that seen in vitro. Certain EMT events are uncoupled from E-cadherin down-regulation and may constitute a novel EMT profile, which warrants further exploration.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Thiery JP, Acloque H, Huang RY et al (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139(5):871–890

    Article  PubMed  CAS  Google Scholar 

  2. Polyak K, Weinberg RA (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9(4):265–273

    Article  PubMed  CAS  Google Scholar 

  3. Huber MA, Kraut N, Beug H (2005) Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol 17(5):548–558

    Article  PubMed  CAS  Google Scholar 

  4. Katz E, Dubois-Marshall S, Sims AH et al (2011) An in vitro model that recapitulates the epithelial to mesenchymal transition (EMT) in human breast cancer. PLoS ONE 6(2):e17083

    Article  PubMed  CAS  Google Scholar 

  5. Schmalhofer O, Brabletz S, Brabletz T (2009) E-cadherin, beta-catenin, and ZEB1 in malignant progression of cancer. Cancer Metastasis Rev 28(1–2):151–166

    Article  PubMed  CAS  Google Scholar 

  6. Gupta PB, Onder TT, Jiang G et al (2009) Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell 138(4):645–659

    Article  PubMed  CAS  Google Scholar 

  7. Hazan RB, Qiao R, Keren R et al (2004) Cadherin switch in tumor progression. Ann N Y Acad Sci 1014:155–163

    Article  PubMed  CAS  Google Scholar 

  8. Prat A, Parker JS, Karginova O et al (2010) Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res 12(5):R68

    Article  PubMed  Google Scholar 

  9. Damonte P, Gregg JP, Borowsky AD et al (2007) EMT tumorigenesis in the mouse mammary gland. Lab Invest 87(12):1218–1226

    Article  PubMed  CAS  Google Scholar 

  10. Peinado H, Olmeda D, Cano A (2007) Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer 7(6):415–428

    Article  PubMed  CAS  Google Scholar 

  11. Elloul S, Elstrand MB, Nesland JM et al (2005) Snail, Slug, and Smad-interacting protein 1 as novel parameters of disease aggressiveness in metastatic ovarian and breast carcinoma. Cancer 103(8):1631–1643

    Article  PubMed  CAS  Google Scholar 

  12. Martin TA, Goyal A, Watkins G et al (2005) Expression of the transcription factors snail, slug, and twist and their clinical significance in human breast cancer. Ann Surg Oncol 12(6):488–496

    Article  PubMed  Google Scholar 

  13. Yook JI, Li XY, Ota I et al (2006) A Wnt-Axin2-GSK3beta cascade regulates Snail1 activity in breast cancer cells. Nat Cell Biol 8(12):1398–1406

    Article  PubMed  CAS  Google Scholar 

  14. Ma L, Young J, Prabhala H et al (2010) miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis. Nat Cell Biol 12(3):247–256

    PubMed  CAS  Google Scholar 

  15. Onder TT, Gupta PB, Mani SA et al (2008) Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Res 68(10):3645–3654

    Article  PubMed  CAS  Google Scholar 

  16. Mikaelian I, Blades N, Churchill GA et al (2004) Proteotypic classification of spontaneous and transgenic mammary neoplasms. Breast Cancer Res 6(6):R668–R679

    Article  PubMed  CAS  Google Scholar 

  17. Moody SE, Perez D, Pan TC et al (2005) The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell 8(3):197–209

    Article  PubMed  CAS  Google Scholar 

  18. Katz E, Dubois-Marshall S, Sims AH et al (2010) A gene on the HER2 amplicon, C35, is an oncogene in breast cancer whose actions are prevented by inhibition of Syk. Br J Cancer 103(3):401–410

    Article  PubMed  CAS  Google Scholar 

  19. Klymkowsky MW, Savagner P (2009) Epithelial-mesenchymal transition: a cancer researcher’s conceptual friend and foe. Am J Pathol 174(5):1588–1593

    Article  PubMed  CAS  Google Scholar 

  20. Tarin D, Thompson EW, Newgreen DF (2005) The fallacy of epithelial mesenchymal transition in neoplasia. Cancer Res 65(14):5996–6000

    Article  PubMed  CAS  Google Scholar 

  21. Droufakou S, Deshmane V, Roylance R et al (2001) Multiple ways of silencing E-cadherin gene expression in lobular carcinoma of the breast. Int J Cancer 92(3):404–408

    Article  PubMed  CAS  Google Scholar 

  22. Weigelt B, Geyer FC, Natrajan R et al (2010) The molecular underpinning of lobular histological growth pattern: a genome-wide transcriptomic analysis of invasive lobular carcinomas and grade- and molecular subtype-matched invasive ductal carcinomas of no special type. J Pathol 220(1):45–57

    Article  PubMed  CAS  Google Scholar 

  23. Arpino G, Bardou VJ, Clark GM et al (2004) Infiltrating lobular carcinoma of the breast: tumor characteristics and clinical outcome. Breast Cancer Res 6(3):R149–R156

    Article  PubMed  Google Scholar 

  24. Megha T, Neri A, Malagnino V et al (2010) Traditional and new prognosticators in breast cancer: Nottingham index, Mib-1 and estrogen receptor signaling remain the best predictors of relapse and survival in a series of 289 cases. Cancer Biol Ther 9(4). doi:10.4161/cbt.9.4.10659

  25. Aitken SJ, Thomas JS, Langdon SP et al (2010) Quantitative analysis of changes in ER, PR and HER2 expression in primary breast cancer and paired nodal metastases. Ann Oncol 21(6):1254–1261

    Article  PubMed  CAS  Google Scholar 

  26. Somner JE, Dixon JM, Thomas JS (2004) Node retrieval in axillary lymph node dissections: recommendations for minimum numbers to be confident about node negative status. J Clin Pathol 57(8):845–848

    Article  PubMed  CAS  Google Scholar 

  27. Kononen J, Bubendorf L, Kallioniemi A et al (1998) Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 4(7):844–847

    Article  PubMed  CAS  Google Scholar 

  28. Come C, Magnino F, Bibeau F et al (2006) Snail and slug play distinct roles during breast carcinoma progression. Clin Cancer Res 12(18):5395–5402

    Article  PubMed  CAS  Google Scholar 

  29. Ye Y, Xiao Y, Wang W et al (2010) ERalpha signaling through slug regulates E-cadherin and EMT. Oncogene 29(10):1451–1462

    Article  PubMed  CAS  Google Scholar 

  30. Christiansen JJ, Rajasekaran AK (2006) Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. Cancer Res 66(17):8319–8326

    Article  PubMed  CAS  Google Scholar 

  31. Thomson S, Petti F, Sujka-Kwok I et al (2011) A systems view of epithelial-mesenchymal transition signaling states. Clin Exp Metastasis 28(2):137–155

    Article  PubMed  CAS  Google Scholar 

  32. Sarrio D, Rodriguez-Pinilla SM, Hardisson D et al (2008) Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Res 68(4):989–997

    Article  PubMed  CAS  Google Scholar 

  33. Taube JH, Herschkowitz JI, Komurov K et al (2010) Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes. Proc Natl Acad Sci USA 107(35):15449–15454

    Article  PubMed  CAS  Google Scholar 

  34. Perez-Moreno M, Fuchs E (2006) Catenins: keeping cells from getting their signals crossed. Dev Cell 11(5):601–612

    Article  PubMed  CAS  Google Scholar 

  35. Logullo AF, Nonogaki S, Pasini FS et al (2010) Concomitant expression of epithelial-mesenchymal transition biomarkers in breast ductal carcinoma: association with progression. Oncol Rep 23(2):313–320

    PubMed  Google Scholar 

  36. Dolled-Filhart M, McCabe A, Giltnane J et al (2006) Quantitative in situ analysis of beta-catenin expression in breast cancer shows decreased expression is associated with poor outcome. Cancer Res 66(10):5487–5494

    Article  PubMed  CAS  Google Scholar 

  37. Mironchik Y, Winnard PT Jr, Vesuna F et al (2005) Twist overexpression induces in vivo angiogenesis and correlates with chromosomal instability in breast cancer. Cancer Res 65(23):10801–10809

    Article  PubMed  CAS  Google Scholar 

  38. Casas E, Kim J, Bendesky A et al (2011) Snail2 is an essential mediator of Twist1-induced epithelial mesenchymal transition and metastasis. Cancer Res 71(1):245–254

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to thank InHwa Um, Danielle Wilson and Helen Caldwell for their technical support throughout this study. We would also like to thank Andy Sims and Richard Meehan for their advice. Clinical materials were obtained through the auspices of the Edinburgh Experimental Cancer Medicine Centre. This work was supported by Breakthrough Breast Cancer and the Scottish Funding Council.

Conflict of interest

The authors declare no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Elad Katz.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dubois-Marshall, S., Thomas, J.S., Faratian, D. et al. Two possible mechanisms of epithelial to mesenchymal transition in invasive ductal breast cancer. Clin Exp Metastasis 28, 811–818 (2011). https://doi.org/10.1007/s10585-011-9412-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10585-011-9412-x

Keywords

Navigation