The mechanistic relationship between immunometabolic complications of obesity and breast cancer is not understood, particularly in African American women, a group that is disproportionately affected. Insulin- resistant obesity features chronic systemic and local inflammation of fat, which has been linked to breast cancer outcomes. However, not all obesity conveys the same risk of cancer. About a quarter of obese African American adults are 'metabolically-healthy' despite their obesity and show reduced cardiovascular and diabetes risks. Recent analyses of Framingham Study population-based data show that risks for obesity- associated cancers, including breast cancer, are also reduced in these subjects. A key feature of these healthy obese adults is a reduced inflammatory profile, both locally in fat and systemically in blood. These data set up our long-term goal: to understand and use the relationships between obesity, inflammation and breast cancer outcomes to reduce the effects of obesity on cancer mortality. We do not know whether 'metabolically-healthy' obese African American women have less inflammation in breast tissue or systemically, or whether immunometabolic status associates with reduced breast cancer risk. Many 'metabolically-abnormal' obese African American women are given metformin to control blood glucose, but we do not know if metformin protects them against breast cancer; the critical studies simply have not been performed. It is urgent to resolve these questions, given the numbers of Americans affected and the high mortality arising from obesity and cancer. Our approach will investigate immunometabolic status and breast cancer in the Black Women's Health Study and use both basic laboratory and epidemiological population data to identify critical mechanisms and pharmacological solutions. Our overall objective is to define the critical immunometabolic mechanisms that stratify cancer risk in obese women, and test hypothesized relationships in cell culture models of breast cancer. Based on new preliminary data, we hypothesize that reduced inflammation in certain obese women protects against breast cancer; and that the standard of care for insulin-resistant obesity, metformin, has value for prevention of breast cancer in African American women. The hypothesis is formulated on the basis of preliminary and published studies of Framingham and BWHS subjects. We undertake three Aims: 1. Determine the immunometabolic factors that stratify obesity-related risk of breast cancer in BWHS subjects. 2. Determine whether inflammatory markers, including crown-like structures in breast adipose tissue and plasma cytokine levels, are associated with 'metabolically-abnormal' obesity as opposed to 'metabolically-healthy' obesity. 3. Determine whether novel inhibitors of inflammation and cancer diminish tumor cell aggressiveness in models of human breast cancer. The proposed research is innovative and important because we are the first to disentangle mechanisms that couple obesity to breast cancer risk. The investigation will have important public health impact because our results will help reduce cancer mortality in a disadvantaged population.
Not all obesity is the same: 'metabolically healthy obese' women, who have normal glucose tolerance and lack metabolic syndrome despite sometimes severe obesity, exhibit reduced risks for obesity-associated cancers, including breast cancer. African American women are more likely to be obese and to experience its inflammatory complications. Therefore, new methods to stratify risk using immunometabolic profiling will have important benefits for improved cancer outcomes in this disadvantaged group, including reduced breast cancer mortality.
|Andrieu, Guillaume; Belkina, Anna C; Denis, Gerald V (2016) Clinical trials for BET inhibitors run ahead of the science. Drug Discov Today Technol 19:45-50|
|Deeney, Jude T; Belkina, Anna C; Shirihai, Orian S et al. (2016) BET Bromodomain Proteins Brd2, Brd3 and Brd4 Selectively Regulate Metabolic Pathways in the Pancreatic Î²-Cell. PLoS One 11:e0151329|
|Ip, Blanche; Cilfone, Nicholas A; Belkina, Anna C et al. (2016) Th17 cytokines differentiate obesity from obesity-associated type 2 diabetes and promote TNFÎ± production. Obesity (Silver Spring) 24:102-12|
|Nicholas, Dequina A; Andrieu, Guillaume; Strissel, Katherine J et al. (2016) BET bromodomain proteins and epigenetic regulation of inflammation: implications for type 2 diabetes and breast cancer. Cell Mol Life Sci :|
|Strissel, Katherine J; Nicholas, Dequina A; Castagne-Charlotin, Myriam et al. (2016) Barriers to Obtaining Sera and Tissue Specimens of African-American Women for the Advancement of Cancer Research. Clin Med Insights Womens Health 9:57-61|
|Andrieu, Guillaume; Tran, Anna H; Strissel, Katherine J et al. (2016) BRD4 Regulates Breast Cancer Dissemination through Jagged1/Notch1 Signaling. Cancer Res :|
|Bethea, Traci N; Rosenberg, Lynn; Castro-Webb, Nelsy et al. (2016) Family History of Cancer in Relation to Breast Cancer Subtypes in African American Women. Cancer Epidemiol Biomarkers Prev 25:366-73|
|Berger, Siv Mari; Gislason, Gunnar; Moore, Lynn L et al. (2016) Associations between metabolic disorders and risk of cancer in Danish men and women--a nationwide cohort study. BMC Cancer 16:133|
|Bertrand, Kimberly A; Bethea, Traci N; Adams-Campbell, Lucile L et al. (2016) Differential patterns of risk factors for early-onset breast cancer by ER status in African American women. Cancer Epidemiol Biomarkers Prev :|
|Boggs, Deborah A; Rosenberg, Lynn; Adams-Campbell, Lucile L et al. (2015) Prospective approach to breast cancer risk prediction in African American women: the black women's health study model. J Clin Oncol 33:1038-44|
Showing the most recent 10 out of 33 publications