Obesity-Induced Mast Cell Infiltration and Activation in Normal Mammary Tissue and Claudin-Low Breast Tumors
Public Deposited- Last Modified
- April 30, 2020
- Creator
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Zattra, Ottavia
- Affiliation: Gillings School of Global Public Health, Department of Nutrition
- Abstract
- Obesity is among the most prevalent conditions worldwide: in the United States alone, more than 60% of the population is either overweight or obese. The condition remains a well-known modifiable risk factor for multiple diseases, including cancer. Obesity is characterized by a low-grade smoldering inflammatory state, which both induces and is sustained by many polarized, pro-inflammatory immune cells. Recent studies have also highlighted the role of the immune system in the genesis and progression of cancer, with many immune cell lineages working to promote angiogenesis, tumor growth and metastasis. One of these immune cells lineages are mast cells (MCs), a type of long-lived myeloid stem cell-derived granulocyte that are traditionally known for their role in the allergic response known as anaphylaxis, but also mediate wound healing and vessel formation. MCs play a crucial role in the tumor microenvironment, by secreting proteases, cytokines and other factors that promote angiogenesis, extracellular matrix degradation and metastasis. Previous studies have reported increased mast cell presence in visceral adipose tissue in obesity. Thus, this study investigated whether obesity promotes mast cell infiltration into and activation within normal mammary tissue and claudin-low breast tumors, an aggressive triple negative subtype of breast cancer. To test our hypotheses, we utilized C57BL/6J and FVB/NJ mouse strains. Female C57BL/6J mice were weaned onto either low fat (LFD, 10% kcal from fat) or high fat (HFD, 60% kcal from fat) diet at 3 weeks of age. At 13 weeks of age, C57BL/6J mice underwent syngeneic orthotopic transplant of M-Wnt claudin-low breast cancer cells into their mammary fat pad. In addition, female FVB/NJ mice were randomized to either LFD or HFD at 8 weeks of age; at 13 weeks of age, mice in a Diet Switch (DS) group were also transitioned from HFD to LFD to induce weight loss prior to tumor injection. FVB/NJ mice underwent syngeneic orthotopic transplant of C3-Tag-luc claudin-low breast cancer cells into their mammary fat pad at 18 weeks of age. We sought to measure mast cell infiltration and activation through histological quantification of mast cell density (cells/mm2), and through quantification of Tryptase β-2 mRNA expression levels, respectively. Relative to tumors, higher mast cell density, as well as higher Tryptase β-2 mRNA expression, was observed in normal mammary of C57BL/6J mice. Importantly, in C57BL/6J mice, higher mRNA expression was also observed across tissues in HFD-fed as compared to LFD-fed mice by two-way ANOVA. In FVB/NJ mice, higher MC density was observed in tumors as compared to normal mammary. Furthermore, higher Tryptase expression was observed in normal mammary tissue upon conditions of obesity, and was significantly reversed with weight loss before tumor development. In summary, these results indicate that low and high fat diets have differential effects on murine models, including body weight and body composition, and that high fat diet may influence mast cell activation in normal mammary tissue, independently of mast cell density. This pilot study offers insights into a potential role of obesity in modulating activation of mast cells, emphasizing the need for future investigation into mast cells as mediators of the relationship between obesity and breast cancer risk or progression.
- Date of publication
- spring 2017
- Keyword
- DOI
- Resource type
- Rights statement
- In Copyright
- Note
- Funding: Dunlevie Honors Undergraduate Research Fund
- Advisor
- Makowski, Liza
- Degree
- Bachelor of Science in Public Health
- Academic concentration
- Nutrition
- Honors level
- Honors
- Degree granting institution
- University of North Carolina at Chapel Hill
- Graduation year
- 2017
- Language
- English
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