Comprehensive genetic and functional characterization of IPH-926: a novel CDH1-null tumour cell line from human lobular breast cancer

J Pathol. 2009 Apr;217(5):620-32. doi: 10.1002/path.2495.

Abstract

Infiltrating lobular breast cancer (ILBC) is a clinically and biologically distinct tumour entity defined by a characteristic linear cord invasion pattern and inactivation of the CDH1 tumour suppressor gene encoding for E-cadherin. ILBCs also lack beta-catenin expression and show aberrant cytoplasmic localization of the E-cadherin binding protein p120-catenin. The lack of a well-characterized ILBC cell line has hampered the functional characterization of ILBC cells in vitro. We report the establishment of a permanent ILBC cell line, named IPH-926, which was derived from a patient with metastatic ILBC. The DNA fingerprint of IPH-926 verified genetic identity with the patient and had no match among the human cell line collections of several international biological resource banks. IPH-926 expressed various epithelial cell markers but lacked expression of E-cadherin due to a previously unreported, homozygous CDH1 241ins4 frameshift mutation. Detection of the same CDH1 241ins4 mutation in archival tumour tissue of the corresponding primary ILBC proved the clonal origin of IPH-926 from this particular tumour. IPH-926 also lacked beta-catenin expression and showed aberrant cytoplasmic localization of p120-catenin. Array-CGH analysis of IPH-926 revealed a profile of genomic imbalances that included many distinct alterations previously observed in primary ILBCs. Spectral karyotyping of IPH-926 showed a hyperdiploid chromosome complement and numerous clonal, structural aberrations. IPH-926 cells were anti-cancer drug-resistant, clonogenic in soft agar, and tumourigenic in SCID mice. In xenograft tumours, IPH-926 cells recapitulated the linear cord invasion pattern that defines ILBCs. In summary, IPH-926 significantly extends the biological spectrum of the established breast cancer cell lines and will facilitate functional analyses of genuine human ILBC cells in vitro and in vivo.

MeSH terms

  • Aged
  • Allelic Imbalance
  • Animals
  • Antigens, CD
  • Base Sequence
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cadherins / deficiency
  • Cadherins / genetics*
  • Cadherins / metabolism
  • Carcinoma, Lobular / genetics*
  • Carcinoma, Lobular / metabolism
  • Carcinoma, Lobular / pathology
  • Carcinoma, Lobular / secondary
  • Cell Line, Tumor
  • Female
  • Humans
  • Karyotyping
  • Mice
  • Mice, Inbred NOD
  • Mutation
  • Neoplasm Proteins / metabolism
  • Neoplasm Transplantation
  • Transplantation, Heterologous

Substances

  • Antigens, CD
  • CDH1 protein, human
  • Cadherins
  • Neoplasm Proteins