Journal of Cancer Research and Clinical Oncology

, Volume 133, Issue 2, pp 83–92 | Cite as

Dominant-negative E-cadherin inhibits the invasiveness of inflammatory breast cancer cells in vitro

  • Hui-Ming Dong
  • Gang Liu
  • Yi-Feng Hou
  • Jiong Wu
  • Jin-Song Lu
  • Jian-Min Luo
  • Zhen-Zhou Shen
  • Zhi-Ming Shao
Original Paper

Abstract

E-cadherin is a transmembrane glycoprotein which mediates epithelial cell-to-cell adhesion function as a tumor suppressor and frequently loss of expression in a wide spectrum of human cancer. However, recent studies demonstrated that E-cadherin was always over-expressed in inflammatory breast cancer (IBC) specimen and cell lines, which is a clinical extreme malignancy of breast cancer. It is hypothesized that the gain and not the loss of the E-cadherin axis contributes to the IBC unique phenotype. To test this assumption, we generated dominant negative mutant E-cadherin high-expression inflammatory breast cancer cells by introduced dominant negative mutant E-cadherin (H-2kd-E-cad) cDNA into human IBC SUM149 cells. Our studies demonstrated that the ability of invasion of SUM149 cells was significantly inhibited by H-2kd-E-cad via down-regulation of MMP-1 and MMP-9 expression. The underlying signal pathway of MAPK phosphorylated Erk 1/2(P44/42) in H-2kd-E-cad-transfected SUM149 cells was significantly down-regulated compared to parental and mock contrast. Our studies provided further functional evidence as the gain of E-cadherin expression dedicated to the IBC malignant phenotype and the blockage of MAPK/Erk activation maybe a promising therapeutic target.

Keywords

E-cadherin Inflammatory breast cancer MMP MAPK 

Notes

Acknowledgments

We thank Dr. Ioannis S. Vizirianakis and Professor Stephen P. Ethier for the plasmid pcDNA3.1(-)Myc/His and the SUM149 cell line This research was supported in part by grants from the Outstanding Young Investigator Award of National Natural Science Foundation of China (No. 30025015), National Natural Science Foundation of China (30371580) and National Key Project of China (No. 2001BA703BO5), and the Grant from Shanghai Science and Technology Committee (03J14019).

References

  1. Albini A (1998) Tumor, endothelial cell invasion of basement membranes. The matrigel chemoinvasion assay as a tool for dissecting molecular mechanisms. Pathol Oncol Res 4:230–241PubMedCrossRefGoogle Scholar
  2. Alpaugh ML, Tomlinson JS, Shao ZM, Barsky SH (1999) A novel human xenograft model of inflammatory breast cancer. Cancer Res 59:5079–5084PubMedGoogle Scholar
  3. Amagai M, Fujimori T, Masunaga T, Shimizu H, Nishikawa T, Shimizu N et al (1995) Delayed assembly of desmosomes in keratinocytes with disrupted classic-cadherin-mediated cell adhesion by a dominant negative mutant. J Invest Dermatol 104:27–32CrossRefPubMedGoogle Scholar
  4. Birchmeier W, Behrens J (1994) Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness. Biochim Biophys Acta 1198:11–26PubMedGoogle Scholar
  5. Braga VM (2002) Cell–cell adhesion and signalling. Curr Opin Cell Biol. 14:546–556CrossRefPubMedGoogle Scholar
  6. Bussemakers MJ, Van Bokhoven A, Tomita K, Jansen CF, Schalken JA (2000) Complex cadherin expression in human prostate cancer cells. Int J Cancer 85:446–450CrossRefPubMedGoogle Scholar
  7. Chambers AF, Matrisian LM (1997) Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst 89:1260–1270CrossRefPubMedGoogle Scholar
  8. Chang C, Werb Z (2001) The many faces of metalloproteases: cell growth, invasion, angiogenesis and metastasis. Trends Cell Biol 11:S37–43PubMedGoogle Scholar
  9. Christofori G, Semb H (1999) The role of the cell-adhesion molecule E-cadherin as a tumour-suppressor gene. Trends Biochem Sci 24:73–76CrossRefPubMedGoogle Scholar
  10. Curran S, Murray GI (1999) Matrix metalloproteinases in tumour invasion and metastasis. J Pathol 189:300–308CrossRefPubMedGoogle Scholar
  11. Egeblad M, Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2:161–174CrossRefPubMedGoogle Scholar
  12. Frixen UH, Behrens J, Sachs M, Eberle G, Voss B, Warda A et al (1991) E-cadherin-mediated cell–cell adhesion prevents invasiveness of human carcinoma cells. J Cell Biol 113:173–185CrossRefPubMedGoogle Scholar
  13. Fukata M, Kaibuchi K (2001) Rho-family GTPases in cadherin-mediated cell–cell adhesion. Nat Rev Mol Cell Biol 2:887–897CrossRefPubMedGoogle Scholar
  14. Giroldi LA, Bringuier PP, Shimazui T, Jansen K, Schalken JA (1999) Changes in cadherin–catenin complexes in the progression of human bladder carcinoma. Int J Cancer 82:70–76CrossRefPubMedGoogle Scholar
  15. Hunt NC, Douglas-Jones AG, Jasani B, Morgan JM, Pignatelli M (1997) Loss of E-cadherin expression associated with lymph node metastases in small breast carcinomas. Virchows Arch 430:285–289CrossRefPubMedGoogle Scholar
  16. Islam S, Carey TE, Wolf GT, Wheelock MJ, Johnson KR (1996) Expression of N-cadherin by human squamous carcinoma cells induces a scattered fibroblastic phenotype with disrupted cell–cell adhesion. J Cell Biol. 135:1643–1654CrossRefPubMedGoogle Scholar
  17. Kleer CG, van Golen KL, Braun T, Merajver SD (2001) Persistent E-cadherin expression in inflammatory breast cancer. Mod Pathol 14:458–464CrossRefPubMedGoogle Scholar
  18. Levine E, Lee CH, Kintner C, Gumbiner BM (1994) Selective disruption of E-cadherin function in early xenopus embryos by a dominant negative mutant. Development 120:901–909PubMedGoogle Scholar
  19. Nawrocki B, Polette M, Marchand V, Monteau M, Gillery P, Tournier JM et al (1997) Expression of matrix metalloproteinases and their inhibitors in human bronchopulmonary carcinomas: quantificative and morphological analyses. Int J Cancer 72:556–564CrossRefPubMedGoogle Scholar
  20. Ozawa M, Ringwald M, Kemler R (1990) Uvomorulin–catenin complex formation is regulated by a specific domain in the cytoplasmic region of the cell adhesion molecule. Proc Natl Acad Sci USA 87:4246–450CrossRefPubMedGoogle Scholar
  21. Park CH, Lee MJ, Ahn J, Kim S, Kim HH, Kim KH et al (2004) Heat shock-induced matrix metalloproteinase (MMP)-1 and MMP-3 are mediated through ERK and JNK activation and via an autocrine interleukin-6 loop. J Invest Dermatol 123:1012–1019CrossRefPubMedGoogle Scholar
  22. Pishvaian MJ, Feltes CM, Thompson P, Bussemakers MJ, Schalken JA, Byers SW (1999) Cadherin-11 is expressed in invasive breast cancer cell lines. Cancer Res 59:947–952PubMedGoogle Scholar
  23. Shao ZM, Nguyen M, Alpaugh ML, O’Connell JT, Barsky SH (1998) The human myoepithelial cell exerts antiproliferative effects on breast carcinoma cells characterized by p21WAF1/CIP1 induction, G2/M arrest, and apoptosis. Exp Cell Res 241:394–403CrossRefPubMedGoogle Scholar
  24. Shibata T, Ochiai A, Gotoh M, Machinami R, Hirohashi S (1996) Simultaneous expression of cadherin-11 in signet-ring cell carcinoma and stromal cells of diffuse-type gastric cancer. Cancer Lett 99:147–153CrossRefPubMedGoogle Scholar
  25. Siitonen SM, Kononen JT, Helin HJ, Rantala IS, Holli KA, Isola JJ (1996) Reduced E-cadherin expression is associated with invasiveness and unfavorable prognosis in breast cancer. Am J Clin Pathol 105:394–402PubMedGoogle Scholar
  26. Sternlicht MD, Werb Z (2001) How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 17:463–516CrossRefPubMedGoogle Scholar
  27. Takeichi M (1993) Cadherins in cancer: implications for invasion and metastasis. Curr Opin Cell Biol 5:806–811CrossRefPubMedGoogle Scholar
  28. Takeichi M (1988) The cadherins: cell–cell adhesion molecules controlling animal morphogenesis. Development 102:639–655PubMedGoogle Scholar
  29. Tlsty TD (1998) Cell-adhesion-dependent influences on genomic instability and carcinogenesis. Curr Opin Cell Biol 10:647–653CrossRefPubMedGoogle Scholar
  30. Tomita K, van Bokhoven A, van Leenders GJ, Ruijter ET, Jansen CF, Bussemakers MJ, Schalken JA (2000) Cadherin switching in human prostate cancer progression. Cancer Res 60:3650–3654PubMedGoogle Scholar
  31. Tomlinson JS, Alpaugh ML, Barsky SH (2001) An intact overexpressed E-cadherin/alpha,beta–catenin axis characterizes the lymphovascular emboli of inflammatory breast carcinoma. Cancer Res 61:5231–5241PubMedGoogle Scholar
  32. van Golen KL, Davies S, Wu ZF, Wang Y, Bucana CD, Root H et al (1999) A novel putative low-affinity insulin-like growth factor-binding protein, LIBC (lost in inflammatory breast cancer), and RhoC GTPase correlate with the inflammatory breast cancer phenotype. Clin Cancer Res. 5:2511–219PubMedGoogle Scholar
  33. Vizirianakis IS, Chen YQ, Kantak SS, Tsiftsoglou AS, Kramer RH (2002) Dominant-negative E-cadherin alters adhesion and reverses contact inhibition of growth in breast carcinoma cells. Int J Oncol 21:135–144PubMedGoogle Scholar
  34. Vleminckx K, Vakaet L Jr, Mareel M, Fiers W, van Roy F (1991) Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell 66:107–119CrossRefPubMedGoogle Scholar
  35. Yao J, Xiong S, Klos K, Nguyen N, Grijalva R, Li P et al (2001) Multiple signaling pathways involved in activation of matrix metalloproteinase-9 (MMP-9) by heregulin-beta1 in human breast cancer cells. Oncogene 20:8066–8074CrossRefPubMedGoogle Scholar
  36. Yap AS (1998) The morphogenetic role of cadherin cell adhesion molecules in human cancer: a thematic review. Cancer Invest 16:252–261PubMedGoogle Scholar
  37. Zhu AJ, Watt FM (1996) Expression of a dominant negative cadherin mutant inhibits proliferation and stimulates terminal differentiation of human epidermal keratinocytes. J Cell Sci 109(Pt 13):3013–3023PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Hui-Ming Dong
    • 1
  • Gang Liu
    • 1
  • Yi-Feng Hou
    • 1
  • Jiong Wu
    • 1
  • Jin-Song Lu
    • 1
  • Jian-Min Luo
    • 1
  • Zhen-Zhou Shen
    • 1
  • Zhi-Ming Shao
    • 1
  1. 1.Department of Breast SurgeryBreast Cancer Institute, Cancer Hospital/Cancer Institute, Fudan UniversityShanghaiPeople’s Republic of China

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