In the United States, over one third of adult women are obese, and one in eight women will be diagnosed with breast cancer in their lifetime. Obesity has been shown to be a risk factor for postmenopausal breast cancer and is associated with increased aggressiveness and poor prognosis regardless of menopausal status. However, the mechanisms involved in the relationship between obesity and breast cancer are still not fully understood. Wnt signaling is often elevated in breast tumors (~60%) and is suspected to play a key role in cancer development. It has been shown that inflammatory cytokines, such as TNF-α, IL-1β, IFNγ, are potential mediators in the regulation of Wnt-signaling. We hypothesize that the low-grade inflammatory state associated with obesity is present in human mammary tissue, stimulates Wnt activity, and thereby leads to the development of breast cancer. In this project, we propose to 1) characterize the inflammatory cytokine profile, including IFN-γ, IL-1β, IL-2, IL-6, IL-8, and TNF-α, in the mammary tissue of normal weight, overweight, and obese postmenopausal women using a high performance electrochemiluminescence immunoassay; 2) determine the influences of the obesity-induced pro-inflammatory cytokines on Wnt-signaling by examining gene expression of seven Wnt-signaling target genes using real-time PCR; and 3) define the causality between TNF-α, one of the mot critical inflammatory cytokines, and Wnt signaling by measuring the gene expression of the Wnt targets in samples from normal to overweight and obese postmenopausal women treated with anti-TNF-α antibody or TNF-α recombinant protein respectively. We expect to define a novel mechanism that obesity mediates the development of postmenopausal breast via inflammation-driven Wnt signaling.
| Identifer | oai:union.ndltd.org:UMASS/oai:scholarworks.umass.edu:masters_theses_2-1285 |
| Date | 23 November 2015 |
| Creators | Roubert, Agathe A |
| 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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