Comprehensive genetic and functional characterization of IPH-926: a novel CDH1-null tumour cell line from human lobular breast cancer.
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.
Christgen
Matthias
M
Institute of Pathology, Hannover Medical School, 30625 Hannover, Germany. Christgen.Matthias@MHHannover.de
Bruchhardt
Henriette
H
Hadamitzky
Catarina
C
Rudolph
Cornelia
C
Steinemann
Doris
D
Gadzicki
Dorothea
D
Hasemeier
Britta
B
Römermann
Daniel
D
Focken
Tim
T
Krech
Till
T
Ballmaier
Matthias
M
Schlegelberger
Brigitte
B
Kreipe
Hans
H
Lehmann
Ulrich
U
D000368:Aged; D022981:Allelic Imbalance; D000818:Animals; D015703:Antigens, CD; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015820:Cadherins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D018275:Carcinoma, Lobular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007621:Karyotyping; D051379:Mice; D016688:Mice, Inbred NOD; D009154:Mutation; D009363:Neoplasm Proteins / Q000378:metabolism; D009368:Neoplasm Transplantation; D014183:Transplantation, Heterologous
D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D009363:Neoplasm Proteins