Abstract
IntroductionDysregulated 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.MethodsTumor 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.ResultsMost 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.ConclusionThe 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.
Highlights
Dysregulated choline metabolism is a well-known feature of breast cancer, but the underlying mechanisms are not fully understood
The majority of xenograft tumors were classified as basallike and luminal B subtypes The expression of ER, PgR and human epidermal growth factor receptor 2 (HER2) receptors of the 34 xenograft models was previously determined by IHC and real-time quantitative reverse transcription-PCR (RT-PCR) methods [6,7,24]
high-resolution magic angle spinning (HR-MAS) magnetic resonance spectroscopy (MRS) and gene expression analyses demonstrated that the amount of Cho, PCho and GPC correlated with the expression of several genes, including choline kinase alpha (CHKA) and glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5), in the Cho metabolism pathway in tissue samples from patient-derived breast cancer xenografts representing luminal-like, basal-like and HER2 enriched breast cancer
Summary
Dysregulated choline metabolism is a well-known feature of breast cancer, but the underlying mechanisms are not fully understood. Most of the existing in vivo preclinical breast cancer models are established from a limited number of cell lines isolated from human tumors grown in cell culture before implantation into immunodeficient animals. These models do not reflect the breast cancer heterogeneity since they usually have a monomorphic, poorly differentiated histology and lack of tissue organization [5]. Patient-derived xenograft models generally maintain key features of the original tumors, including histologic subtype, degree of differentiation, growth pattern, and gene expression profiles, even after several passages in vivo [5,6,7,8,9,10]. The drug response in these models shows a good correlation with the primary patient tumors [5,6,11], and altogether the xenografts are representative model systems for studies of metabolic and genetic patterns in human breast cancer
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