Characterization of a novel breast carcinoma xenograft and cell line derived from a BRCA1 germ-line mutation carrier.
A human tumor xenograft (L56Br-X1) was established from a breast cancer axillary lymph node metastasis of a 53-year-old woman with a BRCA1 germ-line nonsense mutation (1806C>T; Q563X), and a cell line (L56Br-C1) was subsequently derived from the xenograft. The xenograft carries only the mutant BRCA1 allele and expresses mutant BRCA1 mRNA but no BRCA1 protein as determined by immunoprecipitation or Western blotting. The primary tumor, lymph node metastasis, and xenograft were hypodiploid by DNA flow cytometry, whereas the cell line displayed an aneuploidy apparently developed via polyploidization. Cytogenetic analysis, spectral karyotyping, and comparative genomic hybridization of the cell line revealed a highly complex karyotype with numerous unbalanced translocations. The xenograft and cell line had retained a somatic TP53 missense mutation (S215I) originating from the primary tumors, as well as a lack of immunohistochemically detectable expression of steroid hormone receptors, epidermal growth factor receptor, human epidermal growth factor receptor 2 (HER-2), and keratin 8. Global gene expression analysis by cDNA microarrays supported a correlation between the expression profiles of the primary tumor, lymph node metastasis, xenograft, and cell line. We conclude that L56Br-X1 and L56Br-C1 are useful model systems for studies of the pathogenesis and new therapeutic modalities of BRCA1-induced human breast cancer.
Johannsson
Oskar T
OT
Departments of Oncology, University Hospital, Lund, Sweden. oskarjoh@landspitali.is
Staff
Synnöve
S
Vallon-Christersson
Johan
J
Kytöla
Soili
S
Gudjonsson
Thorarinn
T
Rennstam
Karin
K
Hedenfalk
Ingrid A
IA
Adeyinka
Adewale
A
Kjellén
Elisabeth
E
Wennerberg
Johan
J
Baldetorp
Bo
B
Petersen
Ole W
OW
Olsson
Håkan
H
Oredsson
Stina
S
Isola
Jorma
J
Borg
Ake
A
D000782:Aneuploidy; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000737:chemistry / Q000235:genetics* / Q000556:secondary; D018389:Codon, Nonsense; D004273:DNA, Neoplasm / Q000032:analysis; D005260:Female; D005434:Flow Cytometry; D019398:Genes, BRCA1; D018095:Germ-Line Mutation / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D008207:Lymphatic Metastasis / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D009693:Nucleic Acid Hybridization; D032681:Spectral Karyotyping; D014178:Translocation, Genetic; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D018389:Codon, Nonsense; D004273:DNA, Neoplasm