Interplay of choline metabolites and genes in patient-derived breast cancer xenografts.
BACKGROUND
Dysregulated choline metabolism is a well-known feature of breast cancer, but the underlying mechanisms are not fully understood. In this study, the metabolomic and transcriptomic characteristics of a large panel of human breast cancer xenograft models were mapped, with focus on choline metabolism.


METHODS
Tumor specimens from 34 patient-derived xenograft models were collected and divided in two. One part was examined using high-resolution magic angle spinning (HR-MAS) MR spectroscopy while another part was analyzed using gene expression microarrays. Expression data of genes encoding proteins in the choline metabolism pathway were analyzed and correlated to the levels of choline (Cho), phosphocholine (PCho) and glycerophosphocholine (GPC) using Pearson's correlation analysis. For comparison purposes, metabolic and gene expression data were collected from human breast tumors belonging to corresponding molecular subgroups.


RESULTS
Most of the xenograft models were classified as basal-like (N = 19) or luminal B (N = 7). These two subgroups showed significantly different choline metabolic and gene expression profiles. The luminal B xenografts were characterized by a high PCho/GPC ratio while the basal-like xenografts were characterized by highly variable PCho/GPC ratio. Also, Cho, PCho and GPC levels were correlated to expression of several genes encoding proteins in the choline metabolism pathway, including choline kinase alpha (CHKA) and glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5). These characteristics were similar to those found in human tumor samples.


CONCLUSIONS
The higher PCho/GPC ratio found in luminal B compared with most basal-like breast cancer xenograft models and human tissue samples do not correspond to results observed from in vitro studies. It is likely that microenvironmental factors play a role in the in vivo regulation of choline metabolism. Cho, PCho and GPC were correlated to different choline pathway-encoding genes in luminal B compared with basal-like xenografts, suggesting that regulation of choline metabolism may vary between different breast cancer subgroups. The concordance between the metabolic and gene expression profiles from xenograft models with breast cancer tissue samples from patients indicates that these xenografts are representative models of human breast cancer and represent relevant models to study tumor metabolism in vivo.
Maria T
MT
Grinde
Nirma
N
Skrbo
Siver A
SA
Moestue
Einar A
EA
Rødland
Eldrid
E
Borgan
Alexandr
A
Kristian
Beathe
B
Sitter
Tone F
TF
Bathen
Anne-Lise
AL
Børresen-Dale
Gunhild M
GM
Mælandsmo
Olav
O
Engebraaten
Therese
T
Sørlie
Elisabetta
E
Marangoni
Ingrid S
IS
Gribbestad
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002794:Choline / Q000378:metabolism*; D002797:Choline Kinase / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005997:Glycerylphosphorylcholine / Q000378:metabolism*; D006801:Humans; D055432:Metabolomics; D051379:Mice; D009368:Neoplasm Transplantation; D010727:Phosphoric Diester Hydrolases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D010767:Phosphorylcholine / Q000378:metabolism*; D046888:Tissue Array Analysis; D059467:Transcriptome; D014183:Transplantation, Heterologous
D010767:Phosphorylcholine; D005997:Glycerylphosphorylcholine; C517212:CHKA protein, human; D002797:Choline Kinase; D010727:Phosphoric Diester Hydrolases; C038133:glycerophosphodiester phosphodiesterase; D002794:Choline