Skip to main content


Log in

Four human breast cancer cell lines with biallelic inactivating α-catenin gene mutations

  • Preclinical study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript


Mutations of E-cadherin have been identified in half of lobular breast cancers and diffuse-type gastric cancers, two tumor subtypes with remarkably similar pathological appearances including small rounded cells with scant cytoplasm and a diffuse growth pattern. A causal role for E-cadherin gene mutations in the lobular breast cancer phenotype was recently demonstrated in E-cadherin knock-out mice. These observations suggested that another gene in the E-cadherin tumor suppressor pathway might be mutated in lobular breast cancers with wild-type E-cadherin genes. Here, we identified E-cadherin gene mutations exclusively in human breast cancer cell lines that grow with a rounded cell morphology. Using expression analyses and gene mutation analyses, we have identified four biallelic inactivating α-catenin mutations among 55 human breast cancer cell lines. All four α-catenin mutations predicted premature termination of the encoded proteins, and concordantly, none of the four mutant cell lines expressed α-catenin proteins. Importantly, three of the α-catenin mutant cell lines had the rounded cell morphology and all 14 cell lines with the rounded cell morphology had mutations of either E-cadherin or α-catenin. As anticipated, loss of α-catenin protein expression was associated with the lobular subtype in primary breast cancers. Together, our observations suggest that α-catenin may be a new tumor suppressor gene that operates in the E-cadherin tumor suppressor pathway.

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

Similar content being viewed by others


  1. Gumbiner BM (2005) Regulation of cadherin-mediated adhesion in morphogenesis. Nat Rev Mol Cell Biol 6:622–634

    Article  CAS  PubMed  Google Scholar 

  2. van Roy F, Berx G (2008) The cell–cell adhesion molecule E-cadherin. Cell Mol Life Sci 65(23):3756–3788

    Article  CAS  PubMed  Google Scholar 

  3. Berx G, Van Roy F (2001) The E-cadherin/catenin complex: an important gatekeeper in breast cancer tumorigenesis and malignant progression. Breast Cancer Res 3:289–293

    Article  CAS  PubMed  Google Scholar 

  4. Hajra KM, Fearon ER (2002) Cadherin and catenin alterations in human cancer. Genes Chromosomes Cancer 34:255–268

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. Berx G, Cleton-Jansen AM, Nollet F, de Leeuw WJ, van de Vijver M, Cornelisse C, van Roy F (1995) E-cadherin is a tumour/invasion suppressor gene mutated in human lobular breast cancers. Embo J 14:6107–6115

    CAS  PubMed  Google Scholar 

  7. Berx G, Cleton-Jansen AM, Strumane K, de Leeuw WJ, Nollet F, van Roy F, Cornelisse C (1996) E-cadherin is inactivated in a majority of invasive human lobular breast cancers by truncation mutations throughout its extracellular domain. Oncogene 13:1919–1925

    CAS  PubMed  Google Scholar 

  8. Becker KF, Atkinson MJ, Reich U, Huang HH, Nekarda H, Siewert JR, Hofler H (1993) Exon skipping in the E-cadherin gene transcript in metastatic human gastric carcinomas. Hum Mol Genet 2:803–804

    Article  CAS  PubMed  Google Scholar 

  9. Becker KF, Atkinson MJ, Reich U, Becker I, Nekarda H, Siewert JR, Hofler H (1994) E-cadherin gene mutations provide clues to diffuse type gastric carcinomas. Cancer Res 54:3845–3852

    CAS  PubMed  Google Scholar 

  10. Derksen PW, Liu X, Saridin F, van der Gulden H, Zevenhoven J, Evers B, van Beijnum JR, Griffioen AW, Vink J, Krimpenfort P, Peterse JL, Cardiff RD, Berns A, Jonkers J (2006) Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis. Cancer Cell 10:437–449

    Article  CAS  PubMed  Google Scholar 

  11. Graff JR, Herman JG, Lapidus RG, Chopra H, Xu R, Jarrard DF, Isaacs WB, Pitha PM, Davidson NE, Baylin SB (1995) E-cadherin expression is silenced by DNA hypermethylation in human breast and prostate carcinomas. Cancer Res 55:5195–5199

    CAS  PubMed  Google Scholar 

  12. van de Wetering M, Barker N, Harkes IC, van der Heyden M, Dijk NJ, Hollestelle A, Klijn JG, Clevers H, Schutte M (2001) Mutant E-cadherin breast cancer cells do not display constitutive Wnt signaling. Cancer Res 61:278–284

    CAS  PubMed  Google Scholar 

  13. Hollestelle A, Nagel JHA, Smid M, Lam S, Elstrodt F, Wasielewski M, Ng S, French PJ, Peeters JK, Rozendaal MJ, Riaz M, Koopman DG, ten Hagen TLM, de Leeuw HCGM, Zwarthoff EC, Teunisse A, van der Spek PJ, Klijn JGM, Dinjens WNM, Ethier SP, Clevers H, Jochemsen AG, den Bakker MA, Foekens JA, Martens JWM, Schutte M (2009) Distinct gene mutation profiles among luminal-type and basal-type breast cancer cell lines. Breast Cancer Res Treat. doi:10.1007/s10549-009-0460-8

  14. Lei H, Sjoberg-Margolin S, Salahshor S, Werelius B, Jandakova E, Hemminki K, Lindblom A, Vorechovsky I (2002) CDH1 mutations are present in both ductal and lobular breast cancer, but promoter allelic variants show no detectable breast cancer risk. Int J Cancer 98:199–204

    Article  CAS  PubMed  Google Scholar 

  15. Tavassoli FA, Devilee P, International Agency for Research on Cancer, World Health Organization (2003) Pathology and genetics of tumours of the breast and female genital organs. International Agency for Research on Cancer; Oxford University Press (distributor), Lyon, Oxford

  16. Cailleau R, Olive M, Cruciger QV (1978) Long-term human breast carcinoma cell lines of metastatic origin: preliminary characterization. In Vitro 14:911–915

    Article  CAS  PubMed  Google Scholar 

  17. Cailleau R, Young R, Olive M, Reeves WJ Jr (1974) Breast tumor cell lines from pleural effusions. J Natl Cancer Inst 53:661–674

    CAS  PubMed  Google Scholar 

  18. Engel LW, Young NA (1978) Human breast carcinoma cells in continuous culture: a review. Cancer Res 38:4327–4339

    CAS  PubMed  Google Scholar 

  19. Guilford P, Hopkins J, Harraway J, McLeod M, McLeod N, Harawira P, Taite H, Scoular R, Miller A, Reeve AE (1998) E-cadherin germline mutations in familial gastric cancer. Nature 392:402–405

    Article  CAS  PubMed  Google Scholar 

  20. Guilford PJ, Hopkins JB, Grady WM, Markowitz SD, Willis J, Lynch H, Rajput A, Wiesner GL, Lindor NM, Burgart LJ, Toro TT, Lee D, Limacher JM, Shaw DW, Findlay MP, Reeve AE (1999) E-cadherin germline mutations define an inherited cancer syndrome dominated by diffuse gastric cancer. Hum Mutat 14:249–255

    Article  CAS  PubMed  Google Scholar 

  21. Watabe M, Nagafuchi A, Tsukita S, Takeichi M (1994) Induction of polarized cell–cell association and retardation of growth by activation of the E-cadherin-catenin adhesion system in a dispersed carcinoma line. J Cell Biol 127:247–256

    Article  CAS  PubMed  Google Scholar 

  22. Ewing CM, Ru N, Morton RA, Robinson JC, Wheelock MJ, Johnson KR, Barrett JC, Isaacs WB (1995) Chromosome 5 suppresses tumorigenicity of PC3 prostate cancer cells: correlation with re-expression of alpha-catenin and restoration of E-cadherin function. Cancer Res 55:4813–4817

    CAS  PubMed  Google Scholar 

  23. Bullions LC, Notterman DA, Chung LS, Levine AJ (1997) Expression of wild-type alpha-catenin protein in cells with a mutant alpha-catenin gene restores both growth regulation and tumor suppressor activities. Mol Cell Biol 17:4501–4508

    CAS  PubMed  Google Scholar 

  24. Maeno Y, Moroi S, Nagashima H, Noda T, Shiozaki H, Monden M, Tsukita S, Nagafuchi A (1999) Alpha-catenin-deficient F9 cells differentiate into signet ring cells. Am J Pathol 154:1323–1328

    CAS  PubMed  Google Scholar 

Download references


Grant support: Susan G. Komen Breast Cancer Foundation (BCTR0601309), Erasmus MC Mrace 2005 and Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO). We thank Adrian Mombrun and Thierry van de Wetering for technical assistance.

Author information

Authors and Affiliations


Corresponding authors

Correspondence to Antoinette Hollestelle or Mieke Schutte.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 37 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hollestelle, A., Elstrodt, F., Timmermans, M. et al. Four human breast cancer cell lines with biallelic inactivating α-catenin gene mutations. Breast Cancer Res Treat 122, 125–133 (2010).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: