Obesity has reached an epidemic level in the United States. A number of epidemiological studies have established obesity as a critical risk factor for postmenopausal breast cancer (post-BC), whereas a reverse association holds prior to menopause. A significant scientific gap exists in understanding the mechanism(s) underpinning this epidemiological phenomenon, particularly the reverse association between obesity and premenopausal breast cancer (pre-BC). This study aimed to understand how folate metabolism and DNA methylation informs the association between obesity and pre-BC. Fifty normal breast tissue samples were collected from premenopausal women who underwent reduction mammoplasty. We developed and measured the breast tissue folate by a Lactobacillus Casei microbiological assay, and the DNA methylation of LINE-1, a biomarker of genome-wide methylation, and the promoter methylation and gene expression of SFRP1, a tumor suppressor, were measured by pyrosequencing and real-time PCR. We found a high BMI is associated with increased folate level in the mammary tissue, with an increase of 2.65 ng/g of folate per every 5-unit increase of BMI (p < 0.05). The LINE-1 DNA methylation was significantly associated with BMI (p < 0.05), and marginally associated with folate concentration (p = 0.087). For the 8 CpG sites analyzed in the promoter region of the SFRP1 gene, no associations were observed for either BMI or tissue folate (p > 0.05), although a high expression of SFRP1 was observed in subjects with high BMI or high folate (p < 0.05). This study demonstrated that, in premenopausal women, obesity is associated with an increased mammary folate status, genome-wide DNA methylation and SFRP1 gene expression, indicating that the improved folate and epigenetic status is potentially responsible for the reverse association between obesity and pre-BC. More studies are warranted to further understand how obesity mediates pre-BC via altering folate metabolism and DNA methylation.
| Identifer | oai:union.ndltd.org:UMASS/oai:scholarworks.umass.edu:masters_theses_2-1655 |
| Date | 09 July 2018 |
| Creators | Frederick, Armina-Lyn |
| Publisher | ScholarWorks@UMass Amherst |
| Source Sets | University of Massachusetts, Amherst |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Masters Theses |
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