|SUNDARAM, SNEHA - Former ARS Employee|
|RUST, BRET - Former ARS Employee|
Submitted to: Frontiers in Oncology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/13/2021
Publication Date: 9/9/2021
Citation: Yan, L., Sundaram, S., Rust, B.M., Picklo, M.J., Bukowski, M.R. 2021. Mammary tumorigenesis and metabolome in adipose specific monocyte chemotactic protein-1 deficient male MMTV-PyMT mice fed a high-fat diet. Frontiers in Oncology. 11. Article 667843. https://doi.org/10.3389/fonc.2021.667843.
Interpretive Summary: Male breast cancer, while rare, presents as a highly invasive carcinoma with poor prognosis. Obesity is a risk factor for breast cancer. Fat tissue produces many biological active chemicals, including monocyte chemotactic protein-1 (MCP-1), that may promote breast cancer growth. We investigated the effect of fat-derived MCP-1 on mammary tumor growth in a mouse model of male breast cancer, in which MCP-1 was removed from body fat by knocking out the MCP-1 gene from fat tissues. We found that obese mice had a greater tumor growth rate compared to control mice with less body fat. Knocking out the MCP-1 gene from fat resulted in a slower tumor growth rate and smaller mammary tumors in mice. Furthermore, it took a longer time to develop mammary tumors in MCP-1 knockout mice. We conclude that fat-derived MCP-1 contributes to breast cancer development and growth in male mice. Findings from this study suggest that reducing body fat, which will reduce fat-derived chemicals, will be beneficial in breast cancer prevention in men.
Technical 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-produced 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 WT mice, 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). Plasma metabolomic analysis identified 56 metabolites that differed among the four dietary groups. Discriminant analysis along with pathway and network analyses showed that amino acid metabolism (alanine, isoleucine, leucine, phenylalanine, threonine, and valine) and carbohydrate metabolism (fumaric acid, glucuronic acid, hexuronic acid, and malic acid) are the most disturbed in MMTV-PyMT mice. In conclusion, adipose-produced MCP-1 contributes to mammary tumorigenesis in male MMTV-PyMT mice through perturbation of amino acid and carbohydrate metabolism.