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In the United States, breast cancer is the most commonly diagnosed cancer in women, except for skin cancers. The American Cancer Society estimates there will be 268,600 new cases in 2019 alone. It is also the second leading cause of cancer mortality in U.S. women, after lung cancer, with an estimated 41,760 deaths set to occur in 2019. However, worldwide, breast cancer is the most frequently diagnosed cancer in women and the leading cause of female cancer deaths. There are many disparities in breast cancer incidence and prognosis. Among the starkest of these disparities is the difference between African American and Caucasian American women. African American women present with higher rates of aggressive triple-negative subtype, earlier age at diagnosis, and have a 39% higher mortality rate than Caucasian American women. African American women also have higher rates of obesity than Caucasian American women. Obesity and inflammation are also very closely linked to breast cancer. Obesity causes chronic inflammation, and is a risk factor for post-menopausal breast cancer and worse prognosis. This work looks at several effects of obesity-related inflammation in the progression of breast cancer. Bioinformatics was used to explore the differential expression of resistin, a pro-inflammatory cytokine that has 4-fold higher expression in African American women. Due to the pro-inflammatory behavior, and role in adipose tissue, resistin may be a link between obesity, inflammation, and cancer. Resistin was differentially expressed in African American early-stage receptor negative subtypes. It was especially linked to estrogen receptor negative breast cancer subtype. Resistin expression was also higher in triple-negative subtype compared to luminal A subtype, which is hormone receptor positive. The high levels of resistin could contribute to African American breast cancer phenotype and high mortality rates. It may also serve as an early detection biomarker, since it is linked to early stages. Another effect of obesity that was analyzed in this work was the role of macrophages in breast cancer cell-adipocyte crosstalk. Obesity triggers increased infiltration of macrophages into adipose tissue. An innovative cell co-culture system was used to study the paracrine interactions between adipocytes, macrophages, and breast cancer cells, and how they can benefit tumor progression. Macrophage conditioned media intensified the effects of breast cancer cell-adipocyte crosstalk. In this crosstalk, adipocytes become cancer-associated, meaning they become delipidated and increase production of pro-inflammatory cytokines. Breast cancer cells then benefit from this increased inflammation and become more aggressive. Macrophage conditioned media in breast cancer cell and adipocyte co-culture increased tumor cell proliferation and migration compared to co-culture with nonconditioned media. Macrophage conditioned media also increased the expression of pro-inflammatory cytokines by adipocytes, even in the absence of breast cancer cells, although the expression levels were highest with all three cell components. Additionally, in co-culture of adipocytes and breast cancer cells with macrophage conditioned media, adipocytes showed signs of delipidation. Therefore, macrophages contribute to adipocyte inflammation and cancer-association, and help drive tumorigenesis.
Adipocytes, Breast cancer, Disparities, Inflammation, Macrophages, Resistin
Date of Defense
July 18, 2019.
A Dissertation submitted to the Department of Chemistry and Biochemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy.
Includes bibliographical references.
Qing-Xiang Sang, Professor Co-Directing Dissertation; Yi Ren, Professor Co-Directing Dissertation; Debra Fadool, University Representative; Scott Stagg, Committee Member; Oliver Steinbock, Committee Member.
Florida State University
Vallega, K. A. (2019). Effects of Obesity-Related Inflammation on Breast Cancer Progression. Retrieved from http://purl.flvc.org/fsu/fd/2019_Summer_Vallega_fsu_0071E_15362