Adipose monocyte chemotactic protein–1 deficiency reduces high-fat diet-enhanced mammary tumorigenesis in MMTV-PyMT mice

Authors: Sundaram, Sneha; Yan, Lin

Submitted to: Journal of Nutritional Biochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/25/2019
Publication Date: 11/29/2019
Publication URL: https://handle.nal.usda.gov/10113/6785889
Citation: Sundaram, S., Yan, L. 2019. Adipose monocyte chemotactic protein–1 deficiency reduces high-fat diet-enhanced mammary tumorigenesis in MMTV-PyMT mice. Journal of Nutritional Biochemistry. https://doi.org/10.1016/j.jnutbio.2019.108313.
DOI: https://doi.org/10.1016/j.jnutbio.2019.108313

Interpretive Summary: Obesity is a risk factor for breast cancer. Being obese at the time of diagnosis of breast cancer is positively associated with poor prognosis and a greater risk of developing recurrent or metastatic cancer. These devastating aspects of breast cancer directly affect the quality life and survival of the patients. Fat tissue produces many chemicals called adipokines, such as monocyte chemotactic protein-1 (MCP-1), that may have cancer-promoting potentials. In the present study, we investigated the effects of fat-produced MCP-1 on breast tumor growth in mice fed a high-fat, obesogenic diet. We found that feeding mice a high-fat diet increased body fat and enhanced mammary tumor growth compared to mice fed a normal, control diet. This is evidenced by the greater growth rate and the larger size of mammary tumors in mice fed the high-fat diet. Deficiency of MCP-1 in fat tissue (by knocking down the gene responsible for producing MCP-1) reduced body fat and the growth rate and size of mammary tumors, particularly in mice fed the high-fat diet. Furthermore, blood concentrations of other fat-produced cancer-promoting adipokines were lower in mice deficient in MCP-1. Findings from this study indicate that MCP-1 produced by fat tissue contributes, at least partly, to high-fat diet-enhanced mammary tumor growth. We suggest that reduction in MCP-1, through prevention of obesity, may attenuate breast cancer progression particularly in those patients who are obese or overweight.

Technical Abstract: Monocyte chemotactic protein-1 (MCP-1) is an adipokine with demonstrated carcinogenic potential. However, there is no direct evidence that adipose-produced MCP-1 contribute to breast cancer. This study tested the hypothesis that adipose-produced MCP-1 contributes to breast tumorigenesis. In a breast cancer model induced by mouse mammary tumor virus-polyomavirus middle T-antigen (MMTV-PyMT), mice with or without adipose MCP-1 knockdown (designated as Mcp-1-/- or wild-type (WT)) were fed the AIN93G diet or a high-fat diet (HFD) containing 16% or 45% of energy provided by soybean oil. Adipose MCP-1 knockdown was achieved by breeding male mice homozygous for MCP-1fl/fl and heterozygous for the PyMT oncogene (MMTV-PyMT+/MCP-1fl/fl) with female MCP-1fl/fl mice expressing Cre recombinase driven by the adiponectin promoter (MCP-1fl/fl/Adipoq-Cre+). Adipose MCP-1 knockdown reduced Mcp-1 expression in adipose tissue and concentrations of MCP-1 in plasma. Mcp-1-/- mice fed the HFD had less body fat than their WT counterparts. Adipose MCP-1 knockdown attenuated HFD-enhanced mammary tumorigenesis, evidenced by lower mammary tumor progression and tumor volume. Furthermore, Mcp-1-/- mice, regardless of diet, had a longer tumor latency and less tumor weight than WT mice. When fed the HFD, Mcp-1-/- mice, compared to WT mice, exhibited lower plasma concentrations of insulin, proinflammatory cytokines (leptin and resistin), and angiogenic factors (vascular endothelial growth factor and hepatic growth factor). In summary, adipose MCP-1 deficiency attenuated HFD-enhanced MMTV-PyMT mammary tumorigenesis. This attenuation can be attributed to less body adiposity, improvement in insulin sensitivity, and down-regulation in production of pro-tumorigenic inflammation cytokines and angiogenic factors in Mcp-1-/- mice. It concludes that adipose-produced MCP-1 contributes to mammary tumorigenesis in MMTV-PyMT mouse model.