Judith D. Salley

AGE Metabolites: A Biomarker Linked to Cancer Disparity?

Socioeconomic and environmental influences are established factors promoting cancer disparity, but the contribution of biologic factors is not clear. We report a mechanistic link between carbohydrate-derived metabolites and cancer that may provide a biologic consequence of established factors of cancer disparity. Glycation is the nonenzymatic glycosylation of carbohydrates to macromolecules, which produces reactive metabolites called advanced glycation end products (AGE). A sedentary lifestyle and poor diet all promote disease and the AGE accumulation pool in our bodies and also increase cancer risk. We examined AGE metabolites in clinical specimens of African American and European American patients with prostate cancer and found a higher AGE concentration in these specimens among African American patients when compared with European American patients. Elevated AGE levels corresponded with expression of the receptor for AGE (RAGE or AGER). We show that AGE-mediated increases in cancer-associated processes are dependent upon RAGE. Aberrant AGE accumulation may represent a metabolic susceptibility difference that contributes to cancer disparity. Cancer Epidemiol Biomarkers Prev; 23(10); 2186–91. ©2014 AACR.

Abstract A24: Triple-negative breast Cancer risk: Ancestry and immune response

Background: Blacks in the U.S. have the worst breast cancer survival outcomes of any racial/ethnic group in the nation. However, blacks are not a monolithic group but are comprised of several ethnic groups. One such group in particular is the Sea Island or Gullah population of coastal South Carolina, North Carolina, Georgia, and Florida, whose ancestors came from coastal rice-growing areas of Africa. Sea Islanders (SI) have the lowest rates of European (non-Hispanic white) genetic admixture of any U.S. blacks, and are thus a special population who provide a rare opportunity to investigate genetic contributions to the profound ancestrally linked disparities in BC. Purpose: The purpose of this study was to identify, for the first time, frequencies of selected single nucleotide polymorphisms (SNPs) associated with triple-negative breast cancer (TNBC) in these three non-Hispanic population groups: whites, African Americans without Sea Island ancestry (AA), and African Americans with Sea Island ancestry (SI). Methods: Saliva samples were obtained using a mailed kit from a sample of 90 women in SC who had been diagnosed with TNBC in the past 1.5 years, recruited from the three population groups (30 women per group). Four SNPs on the 19p13 locus of BRCA 1 (rs8170, rs4808611, rs2363956, and rs3745185) were evaluated. Results: The percentage of TNBC cases was 6.7% among whites, 4.2% among SI blacks, and 22% among non-SI blacks. After controlling for TNBC status, similar allele frequencies for each SNP were seen in whites and SI blacks, compared to non-SI blacks (p Discussion: The prevalence of triple-negative breast cancer is significantly higher in African American women, and at younger ages, than in white women. Findings by Mukhtar et al. (2011) implicate immune function in the development of this aggressive breast cancer, as higher proliferating cellular nuclear antigen counts and tumor-associated macrophages were associated with hormone receptor-negative tumors and non-white ethnicity. Human populations differ in their transcriptional responses to immune challenges, and immune-responsive regulatory variants have participated in human adaptation by positive selection. Regulatory variants affecting steady-state gene expression and transcriptional responsiveness to immune challenges, particularly those that were viral related, may have been preferentially introduced into African genomes through admixture with Europeans, which may have conferred a natural selection disadvantage to modern blacks without SI ancestry. Such a natural selection disadvantage may mean that different immunologic therapeutic approaches are required for blacks with cancer than for whites with cancer, particularly for more aggressive disease. Citation Format: Marvella E. Ford, Erika T. Brown, David P. Turner, Victoria J. Findlay, Nestor F. Esnaola, Anthony J. Alberg, Susan Bolick, Deborah Hurley, Rita Kramer, Judith D. Salley, Joan E. Cunningham. Triple-negative breast Cancer risk: Ancestry and immune response [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr A24.

Abstract B08: Highlighting the maturation of the MSI/NCI P20 South Carolina Cancer Disparities Research Center Partnership

The South Carolina Cancer Disparities Research Center (SC CaDRe), funded by the NIH/NCI Center to Reduce Cancer Health Disparities (CRCHD) in 2011, is a formal collaboration between the Medical University of South Carolina (MUSC) and South Carolina State University (SCSU, an historically black university). The SC CaDRe focuses on biological mechanisms of disparity in hormone-related cancers (breast and prostate cancer). The Sea Island population plays a prominent role in the three SC CaDRe research projects. The Sea Islanders are an African American ethnic group indigenous to the coastal southeast, with low rates of European American genetic admixture; as such they are ideal for inclusion in biomedical research. Each SC CaDRe research project includes Multiple PIs from MUSC and SCSU. The first research project is titled Biological Implications of DNA Glycation in Prostate Cancer Disparities; the second is titled MicroRNA Mediated Negative Regulation of Caveolin 1 as a Biological Mechanism Driving Breast Cancer Disparities; and the third is titled Feasibility Study of Breast Cancer Candidate Genes in Three Population Groups in South Carolina. The design and results of each project will be presented. The P20 SC CaDRe has led to two funded NIH R21 grants, an R01 grant, an R25E grant, and a DOD research training grant. Three undergraduate students from SCSU and four graduate students from MUSC have participated in SC CaDRe cancer research training, resulting in peer-reviewed publications and presentations at national scientific meetings. As a next step, the SC CaDRe investigators plan to submit an NIH/NCI CRCHD U54 grant application in 2016. Citation Format: Marvella E. Ford, Dennis K. Watson, James Stukes, Mahtabuddin Ahmed, David P. Turner, Ashley Evans Knowell, Victoria J. Findlay, Anita L. Harrison, Kendrea D. Knight, Heidi Varner, Kimberly Cannady, Judith D. Salley. Highlighting the maturation of the MSI/NCI P20 South Carolina Cancer Disparities Research Center Partnership. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr B08.

Abstract C76: Mechanistic implications of advanced glycation end-products to prostate cancer and racial disparity

Poor diet, low income, obesity and a lack of exercise are established lifestyle factors that are known to increase cancer burden and are often more prevalent in African American communities. As our understanding of tumor biology advances, it is becoming increasingly clear that these inter-related lifestyle factors have distinct molecular consequences on the biological make-up of tumors, altering cell signaling events and gene expression profiles to contribute to cancer disparity outcomes such as its earlier development or its progression to more aggressive disease. Sparse information exists about the genetic and biological factors that contribute to differential cancer survival and mortality rates observed in minority populations. A greater understanding of the interplay between risk factors and the molecular mechanisms associated with cancer disparity will significantly impact minority health. Advanced glycation end products (AGEs) are reactive metabolites produced as a by-product of sugar metabolism. Failure to remove these highly reactive metabolites can lead to protein damage, aberrant cell signaling, increased stress responses, and decreased genetic fidelity. Critically, AGE accumulation is also directly affected by our lifestyle choices such as poor diet, low income, obesity and a lack of exercise. We recently reported a potential mechanistic link between AGEs and prostate cancer which may provide a molecular consequence of our lifestyle choices that can directly impact tumor biology and contribute to cancer disparity. We examined circulating and intra-tumoral AGE metabolite levels in clinical specimens and identified a race specific, tumor dependent pattern of accumulation in prostate cancer serum and tumor. Further mechanistic studies in immortalized prostate cancer cell lines show that AGE treatment increases the expression of the receptor for AGEs (RAGE) to activate cancer-associated signaling cascades. Loss of function studies show that AGE mediated increases in cancer associated processes was dependent upon RAGE expression. Significantly, we show that AGEs are secreted into the tumor microenvironment by cancer cells and may function as signaling molecules to promote immune cell recruitment. These data implicate the AGE-RAGE signaling axis as a potential biological mechanism promoting prostate cancer and may represent a biological mechanism promoting prostate cancer disparity. AGE metabolites may have high potential impact as prognostic/diagnostic markers and/or as a novel area of potential therapeutic intervention to reduce cancer disparity. Citation Format: Danzell M. Smith, Dion Foster, Van Phan, Victoria J. Findlay, Lourdes M. Nogueira, Laura Spruill, Mahtabuddin Ahmed, Judith D. Salley, Marvella E. Ford, David P. Turner. Mechanistic implications of advanced glycation end-products to prostate cancer and racial disparity. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr C76.

Abstract A76: MicroRNA mediated negative regulation of caveolin 1 as a biological mechanism driving breast cancer disparities

In South Carolina, mortality differences between African American (AA) and non-Hispanic white (NHW) women breast cancer patients are amongst the highest in the country. Evidence suggests that the observed racial disparity exists independent of socioeconomic and standard of care issues, suggesting a potential biological factor may be involved. The loss of Caveolin-1 (Cav1) in the tumor stromal compartment has emerged as a novel biomarker for predicting poor clinical outcome in all of the most common subtypes of breast cancer, however the mechanism of Cav1 loss is unknown. We identified miR-510 as a novel oncomir and propose that its elevated expression in breast tumors results in stromal Cav1 loss and a subsequent worse outcome. In this study we used luciferase, western blot and quantitative PCR analysis to study Caveolin-1 as a direct target of miR-510. We used a co-culture system to assess crosstalk between epithelial and stromal compartments in vitro and a mouse model to assess this in vivo. Our research shows that Cav1 is a direct target of miR-510 and that overexpression of miR-510 leads to downregulation of Cav1 protein expression, specifically in the stromal compartment. This may be racially significant as our studies also show that miR-510 levels are elevated and Cav1 levels are reduced in AA breast cancer patients compared to their NHW counterparts. Data from our in vivo studies shows that cancer-associated fibroblasts (CAFs) isolated from miR-510 expressing epithelial derived tumors lead to more aggressive tumor growth when co-injected with breast tumor epithelial cells when compared to scrambled control CAF co-injections and breast tumor epithelial cells alone. Our results suggest that elevated miR-510 expression in breast epithelial cells leads to stromal Cav1 loss and is a mechanism driving racial disparity in breast cancer. Citation Format: David P. Turner, Brooke King, Qi Guo, Bobbie Blake, Lourdes M. Nogueira, amanda c. larue, judith d. salley, marvella e. ford, ashley evans-knowell, Victoria J. Findlay. MicroRNA mediated megative regulation of caveolin 1 as a biological mechanism driving breast cancer disparities. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr C32.

Abstract 5581: Advanced glycation end-products are increased in prostate cancer and may promote racial disparity

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA African American cancer patients are more likely to die of their disease than their European counterparts. Our research has identified a potential mechanistic link between carbohydrate derived metabolites and cancer associated pathways which may provide a biological consequence of the socioeconomic and environmental factors that are known to drive cancer health disparity. Glycation is the non-enzymatic glycosylation of sugar moieties to biological macromolecules such as protein and DNA which produces reactive metabolites known as advanced glycation end products (AGEs). AGEs accumulate in our tissues as we grow older and drive many of the complications associated with diseases displaying health disparity including diabetes, metabolic syndrome, Alzheimers, and heart disease. Low income, obesity and an inactive/sedentary lifestyle are established factors driving cancer health disparity. Significantly, apart from their production during normal metabolism, AGEs are also formed through the ingestion of food and by external environmental factors such as lack of exercise. AGE content in the Western Diet has consistently increased over the last 50 years due to increased consumption of sugar laden and cheap processed/manufactured foods which are high in reactive AGE metabolites and can promote obesity. We therefore examined circulating and intra-tumoral AGE metabolite levels in clinical specimens and identified a race specific, tumor dependent pattern of accumulation in prostate cancer serum and tumor. In mouse xenograft models, AGE accumulation was highest in the more aggressive tumors. One way AGEs mediate their deleterious effects is by functioning as ligand for the trans-membrane receptor for AGE (RAGE). In diabetes and other diseases, the AGE-RAGE signaling axis is a pro-inflammatory pathway leading to the upregulation of pro-inflammtory cytokines through increased NFkB activation. Higher AGE levels in African American prostate tumors corresponded with higher RAGE expression and increased NFkB transcriptional activity. In immortalized prostate cancer cell lines AGE treatment increased cancer associated processes and RAGE expression levels. Loss of function studies show that AGE mediated increases in cancer associated processes was dependent upon RAGE expression. These data implicate the AGE-RAGE signaling axis as a potential biological mechanism promoting prostate cancer and indicate that increased AGE accumulation may represent a biological mechanism promoting prostate cancer disparity. AGE metabolites may have high potential impact as prognostic/diagnostic markers and/or as a novel area of potential therapeutic intervention to reduce cancer disparity. Citation Format: Katherine R. Walter, Dion Foster, Victoria Findlay, Lourdes Nogueira, Sadia Robinson, Emily Kistner-Griffin, Laura Spruill, Ryan Kelly, Mahtabuddin Ahmed, Judith Salley, Marvella Ford, David Turner. Advanced glycation end-products are increased in prostate cancer and may promote racial disparity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5581. doi:10.1158/1538-7445.AM2014-5581