Mammary Tumorigenesis and Metabolome in Male Adipose Specific Monocyte Chemotactic Protein-1 Deficient MMTV-PyMT Mice Fed a High-Fat Diet

Abstract

Male breast cancer, while uncommon, is a highly malignant disease. Monocyte chemotactic protein-1 (MCP-1) is an adipokine; its concentration in adipose tissue is elevated in obesity. This study tested the hypothesis that adipose-derived MCP-1 contributes to male breast cancer. In a 2x2 design, male MMTV-PyMT mice with or without adipose-specific Mcp-1 knockout [designated as Mcp-1-/- or wild-type (WT)] were fed the AIN93G standard diet or a high-fat diet (HFD) for 25 weeks. Mcp-1-/- mice had lower adipose Mcp-1 expression than WT mice. Adipose Mcp-1 deficiency reduced plasma concentrations of MCP-1 in mice fed the HFD compared to their WT counterparts. Mcp-1-/- mice had a longer tumor latency (25.2 weeks vs. 18.0 weeks) and lower tumor incidence (19% vs. 56%), tumor progression (2317% vs. 4792%), and tumor weight (0.23 g vs. 0.64 g) than WT mice. Plasma metabolomics analysis identified 56 metabolites that differed among the four dietary groups, including 22 differed between Mcp-1-/- and WT mice. Pathway and network analyses along with discriminant analysis showed that pathways of amino acid and carbohydrate metabolisms are the most disturbed in MMTV-PyMT mice. In conclusion, adipose-derived MCP-1 contributes to mammary tumorigenesis in male MMTV-PyMT. The potential involvement of adipose-derived MCP-1 in metabolomics warrants further investigation on its role in causal relationships between cancer metabolism and mammary tumorigenesis in this male MMTV-PyMT model.

Alteration in Plasma Metabolome in High-Fat Diet-Fed Monocyte Chemotactic Protein-1 Knockout Mice Bearing Pulmonary Metastases of Lewis Lung Carcinoma

“…57,58 The notion that the HFD accelerates glycolysis in LLC-bearing mice is supported by findings from a recent metabolomic comparison in which elevated glucose and decreased 1,5-anhydroglucitol occur in plasma from MMTV-PyMT mice fed a HFD. 18 In the present study, we observed elevations of citric acid, fumaric acid, isocitric acid, succinic acid, and glyceric acid in Mcp-1 -/mice regardless of the diet. Furthermore, the network analysis showed alteration in the citrate cycle pathway when compared Mcp-1 -/mice to WT mice.…”

“…39 In the present study, the decreased valine in Mcp-1 -/mice, particularly those fed the HFD, is consistent with a recent metabolomic analysis showing that plasma level of valine is lower in adiposespecific Mcp-1 deficient MMTV-PyMT mice. 18 Taken together, these findings indicate that the inflammatory cytokine MCP-1 may modulate BCAA metabolism pathways in cancer-bearing mice. Elevations of plasma serine and glycine in mice fed the HFD indicate that the HFD may alter serine and glycine metabolism in LLC-bearing mice.…”

“… 57 , 58 The notion that the HFD accelerates glycolysis in LLC-bearing mice is supported by findings from a recent metabolomic comparison in which elevated glucose and decreased 1,5-anhydroglucitol occur in plasma from MMTV-PyMT mice fed a HFD. 18 …”

“…12 Obesity is related to a greater risk of recurrence and poor prognosis in breast cancer 13,14 and prostate cancer patients 15,16 when compared to patients with normal body weights. Recent animal studies have shown that adipose-derived MCP-1 contributes to mammary tumorigenesis in MMTV-PyMT mice 17,18 and pulmonary metastasis of Lewis lung carcinoma in C57BL/6 mice. 19 The MCP-1 is involved in metabolic homeostasis.…”

Sexual Dimorphism of Skeletal Muscle in a Mouse Model of Breast Cancer: A Functional and Molecular Analysis

“…6,8,11,12 In contrast, male MMTV-PyMT mice display a delayed onset of tumor growth with lower penetrance of metastasis, resembling tumor growth profiles in men, which develop 5 to 10 years later than in women. 13 Gene expression profiling has revealed that PyMT mouse breast tumors model the luminal B molecular subtype of human breast cancer, with overexpression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (Her2/neu). 9,10,13 Overall, these observations reinforce that tumor progression in female and male PyMT mice recapitulates the complex stages and heterogeneity of breast cancer in humans.…”