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Author ORCID Identifier
https://orcid.org/0000-0003-4716-833X
AccessType
Campus-Only Access for Five (5) Years
Document Type
dissertation
Degree Name
Doctor of Philosophy (PhD)
Degree Program
Public Health
Year Degree Awarded
2023
Month Degree Awarded
May
First Advisor
Zhenhua Liu
Second Advisor
Young-Cheul Kim
Third Advisor
Soonkyu Chung
Fourth Advisor
Hang Xiao
Subject Categories
Molecular, Genetic, and Biochemical Nutrition
Abstract
Breast cancer (BC) is the most common cancer worldwide in women and is responsible for a large portion of the global number of cancer deaths. Emerging evidence implicates important role of early-life exposures on cancer development later in life. And epidemiological studies have pointed out the protective effect of childhood overweight/obesity on breast cancer later in life. However, the underlying mechanism remains largely undefined. The aim of this study is to better understand how high-fat diet-induced obesity in early life mediates biological processes relevant to breast tumorigenesis later in life. To achieve this goal, we use C57BL/6 female mice to mimic human lifespan and study the underlying biological process towards beast tumorigenesis. A panel of metabolic parameters, inflammatory cytokines, folate regulators as well as tumorigenic Wnt-signaling-related genes were analyzed through Real-time PCR, Western blot assay, and QuickPlex SQ 120, a chemiluminescence assay. Mammary folate status and DNA methylation level were measured by modified Lactobacillus Casei microbiological folate assay and pyrosequencing. The gut microbiome was sequenced through 16s rRNA sequencing. Our results indicate that HF diet-induced obesity in early life has an overall protective effect on breast tumorigenesis, indicated as suppressed Wnt-signaling target genes later in life through promising epigenetic mechanisms, such as altered mammary folate status and DNA methylation level of DKK1 and IGF-1. Although HF diet in early life induced gut microbiome dysbiosis and mammary metabolic as well as pro-inflammatory microenvironment, which collectively pose a potential risk for breast tumorigeneses. Meanwhile, our findings suggest that the altered mammary metabolic and pro-inflammatory microenvironment are potentially mediated via a gut microbiota-breast axis. In conclusion, improved mammary folate status and epigenetic status represent a promising mechanism for the protective effect of childhood obesity against BC. However, from the perspective of the mammary microenvironment and gut microbiome dysbiosis, childhood obesity still poses a potential risk for breast tumorigenesis. Therefore, further studies are needed to develop better strategies to manage obesity and BC.
DOI
https://doi.org/10.7275/35072163
Recommended Citation
Tang, Ying, "The Impact of High-fat Diet in Early Life on Breast Cancer Development Later in Life" (2023). Doctoral Dissertations. 2862.
https://doi.org/10.7275/35072163
https://scholarworks.umass.edu/dissertations_2/2862
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.