Global Metabolomics Reveals Urinary Biomarkers of Breast Cancer in a MCF-7 Xenograft Mouse Model

Abstract

Global metabolomics analysis has the potential to uncover novel metabolic pathways that are differentially regulated during carcinogenesis, aiding in biomarker discovery for early diagnosis and remission monitoring. Metabolomics studies with human samples can be problematic due to high inter-individual variation; however xenografts of human cancers in mice offer a well-controlled model system. Urine was collected from a xenograft mouse model of MCF-7 breast cancer and analyzed by mass spectrometry-based metabolomics to identify metabolites associated with cancer progression. Over 10 weeks, 24 h urine was collected weekly from control mice, mice dosed with estradiol cypionate (1 mg/mL), mice inoculated with MCF-7 cells (1 × 107) and estradiol cypionate (1 mg/mL), and mice dosed with MCF-7 cells (1 × 107) only (n = 10/group). Mice that received both estradiol cypionate and MCF-7 cells developed tumors from four weeks after inoculation. Five urinary metabolites were identified that were associated with breast cancer; enterolactone glucuronide, coumaric acid sulfate, capric acid glucuronide, an unknown metabolite, and a novel mammalian metabolite, “taurosebacic acid”. These metabolites revealed a correlation between tumor growth, fatty acid synthesis, and potential anti-proliferative effects of gut microbiota-metabolized food derivatives. These biomarkers may be of value for early diagnosis of cancer, monitoring of cancer therapeutics, and may also lead to future mechanistic studies.

Metabolic Trajectories Following Contrasting Prudent and Western Diets from Food Provisions: Robust Biomarkers of Short-Term Changes in Habitual Diet

“…Two other metabolites derived from edible plant sources were also identified by MS/MS ( Figure S8) since they were elevated in urine (FC ≈ 2.5 to 3.8) following a Prudent diet as shown by their urinary metabolic trajectory plots ( Figure S12), namely Ent-G and DHBA. In the case for Ent-G, a MS/MS spectral match based on three characteristic product ions, including a neutral loss of a glucuronide is in close agreement with published data [53]. These urinary metabolites were consistently associated (r ≈ 0.30-0.40, p < 0.05) with fruit, vegetable, vitamin C, and/or total sugar intake, and inversely correlated to total fat (Table 3).…”

Metabolic transformation of breast cancer in a MCF-7 xenograft mouse model and inhibitory effect of volatile oil from Saussurea lappa Decne treatment

“…Mice have distinct genetic backgrounds, and co-housing xenograft with control mice can reduce microbiota variation, besides, using the xenograft mouse model can develop tumors at a similar pace so as to monitor the metabolic response to tumor development in a large sample size. In comparison, transgenic mice can be challenging as not all the mice carrying the transgene develop tumors due to a highly variable latency period (Johnson et al 2013). Therefore, the xenograft model is ideal for identifying biomarkers of human breast cancer.…”

Urinary Metabolites as Biomarkers for Diagnosis of Breast Cancer: A Preliminary Study

“…If leakage into blood can be a primary reason for metabolic change, the same is true for urine, which reflects one further step in metabolic transformation [9]. Mass spectrometry (MS)-based metabolomics is a useful tool for profiling changes in metabolites in urine [10].…”