Separate and combined effects of advanced age and obesity on mammary adipose inflammation, immunosuppression and tumor progression in mouse models of triple negative breast cancer

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  • Smith L.A.
    • Affiliation: Gillings School of Global Public Health, Department of Nutrition
  • McDonell S.B.
    • Affiliation: Gillings School of Global Public Health, Department of Nutrition
  • Craven D.M.
    • Affiliation: Gillings School of Global Public Health, Department of Nutrition
  • Rainey M.A.
    • Affiliation: Gillings School of Global Public Health, Department of Nutrition
  • Cozzo A.J.
    • Affiliation: Gillings School of Global Public Health, Department of Nutrition
  • Carson M.S.
    • Affiliation: Gillings School of Global Public Health, Department of Nutrition
  • Glenny E.M.
    • Affiliation: Gillings School of Global Public Health, Department of Nutrition
  • Sheth N.
    • Affiliation: Gillings School of Global Public Health, Department of Nutrition
  • Rezeli E.T.
    • Affiliation: Gillings School of Global Public Health, Department of Nutrition
  • Montgomery S.A.
    • Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine
  • Bowers L.W.
    • Affiliation: Gillings School of Global Public Health, Department of Nutrition
  • Coleman M.F.
    • Affiliation: Gillings School of Global Public Health, Department of Nutrition
  • Hursting S.D.
    • Affiliation: Gillings School of Global Public Health, Department of Nutrition
Abstract
  • Introduction: Advanced age and obesity are independent risk and progression factors for triple negative breast cancer (TNBC), which presents significant public health concerns for the aging population and its increasing burden of obesity. Due to parallels between advanced age- and obesityrelated biology, particularly adipose inflammation, we hypothesized that advanced age and obesity each accelerate mammary tumor growth through convergent, and likely interactive, mechanisms. Methods: To test this hypothesis, we orthotopically transplanted murine syngeneic TNBC cells into the mammary glands of young normoweight control (7 months), young diet-induced obese (DIO), aged normoweight control (17 months), and aged DIO female C57BL/6J mice. Results: Here we report accelerated tumor growth in aged control and young DIO mice, compared with young controls. Transcriptional analyses revealed, with a few exceptions, overlapping patterns of mammary tumor inflammation and tumor immunosuppression in aged control mice and young DIO mice, relative to young controls. Moreover, aged control and young DIO tumors, compared with young controls, had reduced abundance ofcytotoxic CD8 T cells. Finally, DIO in advanced age exacerbated mammary tumor growth, inflammation and tumor immunosuppression. Discussion: These findings demonstrate commonalities in the mechanisms driving TNBC in aged and obese mice, relative to young normoweight controls. Moreover, we found that advanced age and DIO interact to accelerate mammary tumor progression. Given the US population is getting older and more obese, age- and obesity-related biological differences will need to be considered when developing mechanism-based strategies for preventing or controlling breast cancer.
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Resource type
  • Article
License
  • Attribution 4.0 International
Journal title
  • Frontiers in Oncology
Journal volume
  • 12
Language
  • English
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  • Publisher
Funder
  • National Cancer Institute, NCI; Breast Cancer Research Foundation, BCRF: BCRF 22-073, R35CA197627
ISSN
  • 2234-943X
Publisher
  • Frontiers Media S.A.

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