AbstractAfrican American Research Articles

Abstract C66: Insulin-like growth factor binding protein-6 is differentially methylated in African American, African, and Amish HapMap cell lines

Abstract African American women, while having lower lifetime incidence of breast cancer (BrCa) than Caucasian women, have higher BrCa mortality rates, partially due to a higher incidence of the more aggressive, basal-like molecular subtype of BrCa. Correlations of this subtype within African ancestral groups suggest a potential link to African Ancestry and basal-like BrCa. While socioeconomic factors may also play a role in higher mortality rates, there is mounting evidence that the differential epigenetic regulation of cancer genes may also contribute to this disparity. To address this, our lab is investigating the epigenetic regulation of genes in the insulin-like growth factor pathway using qPCR, Immunohistochemistry (IHC) and Bisulfite-DNA Sequencing. This presentation specifically highlights novel data on the expression of insulin-like growth factor binding protein-6 (IGFBP-6), an IGF-II regulator and agent of cell proliferation, which has been shown previously to be epigenetically modified in cancer cells. Our qPCR and IHC data demonstrates higher IGFBP-6 transcription and protein expression in basal-like BrCa cells when compared to normal breast and ER+ BrCa cells. To address potential ancestry-specific expression, we also evaluated IGFBP-6 expression in African and African-American HapMap lymphoblast cell lines compared to CEPH-European (Amish) cell lines. Both qPCR and IHC data indicate higher overall expression of this gene in African lineages. Lastly, we have measured the differential methylation in two regions of the IGFBP-6 CpG island among African, African-American, and Amish cell lines. We show that IGFBP-6 methylation correlates with the expression patterns. Differential methylation could be due to Ancestral-Specific polymorphisms in this region, altering potential methylation sites. We conclude that the distinct levels of IGFBP-6 expression and promoter methylation in African and African-American cell lines may correspond to the increased incidence of basal-like BrCa in these populations, due to prolonged half-life and activity of the IGF-II growth signal. Our future studies include evaluation of whether this epigenetically-mediated up-regulation of IGFBP-6 directly leads to the excessive proliferation of basal-like tumors. Citation Format: DeJuana Ford, Briana Bennett, Myrielis Rivera, Rupali Hire, Melissa Davis. Insulin-like growth factor binding protein-6 is differentially methylated in African American, African, and Amish HapMap cell lines. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr C66. doi:10.1158/1538-7755.DISP13-C66

Abstract C16: Feasibility study: Protein profiling of primary breast cancers from premenopausal women

Abstract African American women are more likely to be diagnosed with aggressive breast cancer at a younger age, have a higher risk of death, and have a higher prevalence of obesity than their Caucasian counterparts. Moreover, African American (AA) women diagnosed with triple-negative breast cancer have the lowest survival rates of all racial/ethnic groups. Although these disparities have been attributed to differences in biology, family and reproductive history, mammographic breast density, body mass index, access to healthcare, diet and environment, more etiologic studies are needed to elucidate the complex association between race, biologic factors, and socioeconomic factors. In the present study, we tested the feasibility of using high-throughput reverse phase protein microarray to identify protein(s) that are differentially expressed in the primary invasive breast cancers of premenopausal Caucasian and African American women. We examined the expression of 60 phosphorylated, total, and cleaved proteins in microdissected epithelial cells from 26 pre-treatment primary breast cancers. The impact of obesity on protein expression was also considered by stratifying samples into non-obese and obese based on a body mass index (BMI). Samples that come from women with BMI < 30 kg/m2 are classified as non-obese, while those with BMI ≥ 30 kg/m2 are considered obese. All statistical analyses were done using SAS Enterprise Guide 5.1 (SAS Institute, Cary, NC). For comparison of 2 groups, t tests were used for continuous variables and Fisher exact tests for categorical variables. ANOVA was used for comparison of more than 2 groups. Two-tailed p-value < 0.05 was considered statistically significant. Unsupervised hierarchical clustering analysis was performed on log 2-transformed values for each protein endpoint, using average linkage of the Pearson correlation coefficient. In this exploratory study, 58% of the primary breast cancers come from Caucasian women, while 42% of the samples come from AA women. The mean age and BMI for the two groups of women did not differ significantly. While the majority of the samples were of luminal subtypes, the triple-negative breast cancers were represented in majority of AA women. The expression of MEK1/2 S217/S221, PKC pan beta S660, and total PTEN were significantly higher in Caucasian women. When the impact of breast cancer subtypes (triple-negative vs. luminal A) on protein expression was examined, only total PTEN was statistically significant. Given the role of obesity in breast cancer, we determined which proteins are differentially expressed in non-obese and obese samples. Few components of the insulin and insulin-like growth factor and inflammatory signaling pathways (e.g. PTEN, acetyl CoA carboxylase, PKC pan beta S660, Stat3) were highly expressed in samples of obese women. This preliminary data demonstrates (a) the feasibility of mapping cell signaling networks in limited number of pre-treatment samples from premenopausal women and (b) the potential of future proteomic and larger cohort studies to identify which women will likely benefit from combination of targeted agents. Citation Format: Catherine Ibarra Drendall, William Barry, Corinne Ramos, Nora Tolbert, Joseph Geradts, Emanuel Petricoin, Victoria Seewaldt. Feasibility study: Protein profiling of primary breast cancers from premenopausal women. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr C16. doi:10.1158/1538-7755.DISP13-C16

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

Abstract 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 (AGE's). AGE's accumulate in our tissues as we grow older and drive many of the complications associated with diseases displaying health disparity including diabetes, metabolic syndrome, Alzheimer's, 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, AGE's 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 AGE's 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

Abstract 263: African American prostate cancer incidence rates inside and outside of zinc zones

Abstract African American males experience disproportionately higher prostate cancer incidence rates versus all other ethnic groups in the North American continent. Data indicates a decreased expression of hZIP1 zinc transporter in African American prostate tissue. Research demonstrates zinc deficiency in-vitro promotes a pro-metastatic dis-regulation of cell cycle and apoptotic processes. Research also demonstrates zinc transporter over-expression in-vitro promotes decreased pro-metastatic and anti-apoptotic activity and sensitization to ligand mediated cell death. Starting from this molecular premise, we examined the relationship between at risk populations’ proximity to zinc mines and incidence rates: hypothesizing a correlation between decreased rates within proximity to zinc mines. Data was requested from cancer registries where zinc mines were located, though only Arizona data was used. Using a combination of excel, basic image capture techniques and radius creating websites, a 100-mile radius was arbitrarily created around Ruby, Arizona where the now abandoned Montana mine is located. Counties in the state of Arizona were divided into those that fell within this radius, or outside of it. Weighted age adjusted incidence rates were then determined for each county for a given ethnic group. Averaged weighted age adjusted rates were then determined for the counties within the radius and outside. These rates were compared within each ethnic group, though one final comparison was made for all ethnicities within and outside of the radius. Maps containing additional zinc mines, locations of aquifers and main streams and the radius were super-posed to visualize the topological relationships of these elements. Our results show that every ethnic group experienced the same decrease in averaged weighted age adjusted prostate cancer incidence rates within the 100-mile radius of the zinc mine versus outside. The same result occurred when all ethnic groups were used simultaneously to compare rate differences on either side of the radius boundary. As expected, African Americans experienced the highest incidence rates within their at risk group. Asian / Pacific Islanders experienced the lowest incidence rates within their at risk group. There appears to be a correlation between the proximity of at risk populations to zinc mines and decreased prostate cancer incidence rates. The geological maps manipulated in this study provide reasonable insight into the passage of zinc from abandoned mining operations into streams and groundwater. It is from these resources that public and private wells (as well as municipal systems) draw water for human use. This basic epidemiological inquiry macroscopically mirrors the established molecular premises and leads to a holistic perspective on the subject. More rigorous statistical analyses need be performed on these data in order to properly support these conclusions. Note: This abstract was not presented at the meeting. Citation Format: Jiro D. Mckinnis, Hao Nguyen. African American prostate cancer incidence rates inside and outside of zinc zones. [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 263. doi:10.1158/1538-7445.AM2014-263

Sorrow as the Longest Memory of Neglect

ABSTRACT African American history and the history of antiblack violence in this country have been plagued with different modes of forgetting and outright neglect. As a result, absence, silence, and breakages mark a particular layer and structure of memory that contextualizes this form of neglect. In this article, I use the work of Billie Holiday, W. E. B. Du Bois, and Walter Benjamin to argue that the more we have objects of memory of the African American past, the more antipathy toward present antiblack violence grows. I show that African American memory of antiblack violence has been marked by an aesthetic of sorrow just as much as it has been an intrusion into the public space. I further argue that it is important to critique the function of neglect and to reenvision the political power of allegorical modes of memory not only to provide a context for what is neglected but to emphasize that this neglect is a symptom of a newly unfolding crisis.

How do African American men rate their health care? An analysis of the consumer assessment of health plans 2003-2006.

African American (AA) men remain one of the most disconnected groups from health care. This study examines the association between AA men's rating of health care and rating of their personal physician. The sample included 12,074 AA men aged 18 years or older from the 2003 to 2006 waves of the Consumer Assessment of Healthcare Providers and Systems Adult Commercial Health Plan Survey. Multilevel models were used to obtain adjusted means rating of health care systems and personal physician, and the relationship of ratings with the rating of personal physician. The adjusted means were 80 (on a 100-point scale) for most health ratings and composite health care scores: personal physician (83.9), specialist (83.66), health care (82.34), getting needed care (89.57), physician communication (83.17), medical staff courtesy (86.58), and customer service helpfulness (88.37). Physician communication was the strongest predictor for physician rating. AA men's health is understudied, and additional research is warranted to improve how they interface with the health care system.

Students from Underrepresented Racial and Ethnic Groups Entering the Dental Hygiene Profession

African American, Hispanic/Latina, and American Indian/Alaska Native persons are markedly underrepresented racial and ethnic groups (UREG) in the dental hygiene profession. The purpose of this study was to survey UREG dental hygiene students to determine their perceptions of the barriers and facilitators that influenced their decision to enter the dental hygiene profession. Participants were eighty-four UREG students attending entry-level dental hygiene programs across the state of California. We conducted face-to-face interviews using a survey guide that consisted of forty-two mostly closed-ended questions. Most (57 percent) participants reported that they had either perceived or experienced barriers: primarily costs associated with the program and the lack of role models in their race/ethnicity. Almost all participants reported that there had been a person, mainly a dental professional, who influenced them to become a dental hygienist; 62 percent of these individuals were reported to be from a similar UREG group as the participant. Funding (57 percent) and emotional support from family and friends (87 percent) were the predominant facilitators employed by the participants to overcome barriers. Based on these results, we recommend three strategies to recruit more UREG students into the dental hygiene profession: more extensive outreach programs, enhanced mentoring by UREG dental professionals, and a modified admission process.

Engaging African American and Latino Adolescent Males Through School-Based Health Centers

African American and Latino males are less likely to seek mental health services and obtain adequate care than their White counterparts. They are more likely to receive mental health services in school-based health centers (SBHCs) than in other community-based setting. The purpose of this article was to understand the issues and reasons these adolescents sought mental health services at SBHCs and what their perceptions of the services were. A content analysis of 22 individual interviews was conducted using Krippendorff's method. Five themes emerged from the analysis of the data: the burdens and hurdles of my life, the door is always open, sanctuary within chaos, they get to us, and achieve my best potential. Each of the themes was explored in detail with rich quotations from the adolescents. The findings illuminated the daily struggles these adolescents faced and the impact mental health services in SBHCs had on their daily lives.

Italian American and African American Encounters in the City and in the Suburb

Italian American and African American relations have generally been characterized as hostile. The two groups are most often seen as encountering each other in urban centers of the Northeast. This article explores the sources of Italian American hostility against African Americans in the pre- and postwar era cities to better understand the underpinnings of racial conflict. At the same time, it highlights the complex relationship between the two groups that could include positive interaction as well as conflict and take place within the suburbs as well as within the cities. The article presents a preliminary case study of suburban Montclair, New Jersey, where from the early 1900s well into the postwar era, African Americans and Italian Americans shared neighborhoods, schools, and, to differing degrees, an outsider status that contributed to generally harmonious relations. The findings suggest that local studies that reveal specific sources of tension or peaceful coexistence can lead to a fuller understanding of relations between these two groups and interethnic/interracial relations in general.

Social Relationships of African American and Hispanic Older Assisted Living Residents: Exploring the Role of Race and Ethnicity

African American and Hispanic older adults are underrepresented in assisted living communities, so little is known about how they experience social relationships in these settings. The purpose of the study was to explore resident-to-resident and resident-to-staff relationships experienced and perceived by African American and Hispanic older residents in assisted living settings. In-depth interviews with 15 African American and 15 Hispanic older adults were conducted in seven assisted living communities in Central Florida. Three salient themes emerged using a grounded theory approach: formation of relationships: emotional vs. instrumental support; language as a facilitator or barrier; and avoidance of inter-racial relationships. Implications for providing culturally competent services in assisted living communities with diverse populations are discussed.

Eating Behaviors Among Early Adolescent African American Girls and Their Mothers

African American (AA) girls aged 10-12 living in urban communities designated as food deserts have a significantly greater prevalence of overweight and obesity than girls that age in the general population. The purpose of our study was (a) to examine the agreement in nutritional intake between AA girls aged 10-12 and their mothers and (b) to determine if the girls' weight categories were associated with their or their mothers demographic characteristics, eating behaviors, nutritional intake, and health problem. A cross-sectional descriptive study was conducted in predominantly low-income AA communities in Chicago. Forty-three dyads of early adolescent AA girls and their mothers responded to food frequency and eating habits questionnaires. There was a strong and significant correlation between mother's and daughter's kilocalories consumed (r = .61). Our study suggests that interventions aimed at improving eating behaviors in early adolescent AA girls should include their mothers.

Abstract 501: Effect of estrogen receptor beta isoforms on the function of estrogen receptor beta in estrogen recpetor alpha negative breast cancer cell lines.

Abstract African American (AA) women with breast cancer are more likely to be diagnosed at a more advanced stage of the disease, have a higher recurrence rate and a poorer prognosis than Caucasian (CA) women. African American women are more often diagnosed with high-grade breast tumors at an earlier age (pre-menopausal), most of which are negative for the estrogen and progesterone receptors (ER-, PR-). These factors result in a higher mortality rate among AA breast cancer patients. This survival disparity can be attributed to socioeconomic status and other related factors, however, there are biological factors that may also be involved. The insulin-like growth factor II (IGF-II) plays a crucial role in fetal and cancer development by signaling through the IGF-I receptor (IGF-IR), the insulin receptor (Ins-R) and also crosstalk with the estrogen receptor alpha (ER-α). Compared to CA women, AA women have an increased level of proIGF-II expression in breast tissues and higher signaling activation through the IGF-1 and Ins-R. Studies have shown that the estrogen receptor beta (ER-β) is also expressed in a majority of breast cancers. The estrogen receptor (ER) as well as the progesterone receptor and Her2Neu have been the most common markers used for determining breast cancer status. Most research done in breast cancer as it pertains to the ER status has mainly been done in cells and tissues expressing the Estrogen Receptor Alpha (ER-α). However, with its discovery in 1996, the Estrogen Receptor Beta (ER-ß) has lead to a better understanding the breast cancer disease. Studies have shown that the estrogen receptor beta (β) is expressed in a majority of breast cancers, including cancers designated as ER negative (ER-). The tumor suppressing function of ER-β has been described based on its interaction with ER-α, however it's function in the absence of ER-α has not been clearly assessed. ER-β has 5 isoforms of which ER-β isoform 5 (ER-β5) is the most abundantly expressed among AA women with triple negative breast cancer. ER-β5 expression is associated with a poor prognosis and decreased survival of breast cancer patients. Therefore, we hypothesize that the heterodimerization and subsequent activation of ER-β with its isoforms, mainly ER-β5, leads to a suppression of its function in breast cancers not expressing ER-α, thus preventing cell death. To test this hypothesis we analyzed the basal expression of ER-β and all of its isoforms (ER- β1-5) in AA and CA normal and breast cancer cell lines. The expression of ER-β5 increased in cells lines in response to insulin like growth factor-II (IGF-II). IGF-II promotes the phosphorylation of ER-β and ER-β5 and may regulate the ER-β signaling pathway in ER-α negative cell lines. Citation Format: Chane’ N. O'Bannon. Effect of estrogen receptor beta isoforms on the function of estrogen receptor beta in estrogen recpetor alpha negative breast cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 501. doi:10.1158/1538-7445.AM2013-501

The Eastland Prostate Cancer Survey: Instrument Development and Psychometric Testing

African-American (AA) women could be instrumental in communicating positive prostate screening behavior to the significant males in their lives. However, little is known about AA women's prostate cancer attitudes, perceived behavioral control, subjective norms, intentions, behaviors, and knowledge regarding prostate cancer screening. This study describes the development and psychometric testing of the Eastland Prostate Cancer Survey (EPCS). A nonexperimental, correlational study with 200 AA women was used to test the psychometric properties of the six-subscale EPCS with 66 items. Construct validity, internal consistency, and test-retest reliability for the EPCS were acceptable and resulted in an eight-subscale EPCS with 56 items. Cronbach's alphas for the subscales ranged from 0.69 to 0.92. The EPCS is a culturally sensitive, gender-relevant instrument that could be used by community health providers to develop community health programs aimed at engaging AA women in the promotion of prostate cancer screening for AA men.

Abstract A35: Metabolomic profiling and the biochemical basis of prostate cancer racial disparity.

Abstract African American (AA) men have an approximately 60% higher incidence of prostate cancer and are at 2 times greater risk of dying of prostate cancer than European Americans (EA). Environmental and socio-economic factors as well as a number of genetic alterations have been previously interrogated as possible explanations for this disparity. Currently, little is known about the specific biological pathway differences in prostate cancer between AA and EA men that may help explain the greater burden borne by AA men with this disease. In this study, we seek to unravel and compare the prostate cancer metabolome of AA and EA men by employing state of the art metabolomic profiling and bioinformatic techniques. Based on the premise that metabolites are end products of enzyme action, we sought to identify a racially distinct biochemical signature for prostate cancer. Fifty-six prostate cancer tissue samples from AA and EA men and their adjacent benign tissues (i.e., matched normal/tumor pairs) were analyzed using an unbiased liquid chromatography-coupled mass spectrometry approach. Differential metabolites were mapped into pathways and combined with bioinformatics-based bioprocess mapping to categorize metabolic differences observed in cancers of AA and EA origin. Our data indicate a specific and largely mutually exclusive metabolic signature for AA and EA derived prostate cancers. These findings may have important clinical implications and, importantly, shed new light on the biological basis of prostate cancer racial disparity. Citation Format: Shaiju Kakkandan VareedKatrin Panzitt, Sumanta Basu, Vasanta Putluri, Tiffany Dorsey, Tiffany Wallace, Nagireddy Putluri, Sayeeduddin Mohammed, Michael Ittmann, Rick Kittles, George Michailidis, Stefan Ambs, Ganesh Palapattu, Arun Sreekumar. Metabolomic profiling and the biochemical basis of prostate cancer racial disparity. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr A35.

Abstract 3913: Estrogen receptor beta and estrogen receptor beta 5 in triple negative breast cancer cells: IGF-II role in regulation of estrogen receptor beta 5

Abstract African American (AA) women with breast cancer are more likely to be diagnosed at a more advanced stage of the disease, have a higher recurrence rate and a poorer prognosis than Caucasian (CA) women. They also are more often diagnosed with high-grade breast tumors at an earlier age (pre-menopausal), most of which are negative for the estrogen and progesterone receptors (ER-, PR-). These factors result in a higher mortality rate among AA breast cancer patients. Our lab has demonstrated that AA women have increased levels of IGF-II coupled with lower levels of the IGF-II receptor needed to degrade IGF-II, thus leading to higher IGF-Ii signaling in contrast to CA women. AA women also have a higher expression of the insulin receptor A versus insulin receptor B when compared to CA women, which increases proliferation and decreases metabolic effects (Singh et. al 2011). We have also shown that IGF-II activates the estrogen receptor alpha (ER-α) and estrogen receptor beta (ER-α) in the absence of the estrogen ligand (Richardson et. Al 2011). When co-expressed, ER-α counteracts the proliferative function of ER-α, however the role of ER-α in breast cancer is different in ER-α negative compared to ER-α positive tumors. Furthermore, there are 5 different isoforms of ER-α, of which ER-Δ5 is the most abundantly expressed form in AA women. Since IGF-II activates ER-α and ER-Δ5 is associated with increased mortality and decreased time recurrence, we have designed a study to determine if IGF-II regulates ER-Δ5. We hypothesize that in the absence of ER-α, ER-α may activate the ER-α signaling pathway, and that the elevated expression of ER-Δ5 and its heterodimerization with of ER-α1 contributes to the overall survival disparity. To test this hypothesis we characterized the levels of phophorylated ER-α (pER-α) and compared them to IGF-II levels in triple negative breast cancer cells and normal triple negative epithelial cells. IGF-II levels were analyzed using western blotting for protein, and RT-PCR for mRNA. AA women have a higher expression of IGF-II in both malignant and normal cells, and comparably higher levels of expression of the active form of ER-α when compared to CA breast cancer cell lines. IGF-II stimulation promoted the translocation of ER-Δ5 to different cellular compartments. We propose that ER-Δ5 impairs the inhibitory effects of ER-α and thus may contribute to the survival disparity among AA breast cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3913. doi:1538-7445.AM2012-3913

Abstract SY09-02: Molecular mechanisms in prostate cancer in African Americans

Abstract African American men have long been known to have the highest rates of prostate cancer (PCa) in the world. In addition, age adjusted mortality rates from PCa patients are two times worse among African Americans (AA) than Caucasians (CA). The reasons for the disparity in PCa risk, incidence, clinical progression, and disease-specific death are still controversial. In addition to socioeconomic and environmental factors, such as diet, access to care, and screenings, a biologically more aggressive cancer is proposed as one important explanation for the racial disparity observed in AA men. Androgens and the androgen receptor pathway are well established key regulators of aggressive PCa behavior. Using a novel proteomic pathway analysis comparing the distinct signal pathway and network proteins different between AA and CA PCa, we identified a number of markers including stem/progenitor cell and EMT related proteins that are overexpressed in PCa among AA. Our ongoing study indicates a novel link among Notch, WNT and androgen receptor (AR) pathways. In contrast to increase in epithelial AR, our data revealed a decrease in the expression of the stromal AR in AA PCa compared to CA PCa. Androgen and its receptor inhibit proliferation of prostate stromal cells through transcriptional suppression of cyclin B1. Mechanistically, the negative regulation of cyclin B1 by AR is mediated through switching between E2F1 and E2F4 on the promoter of cyclin B1. E2F1 binds to cyclin B1 promoter and maintains its expression and subsequent cell cycle progression in AR negative stromal cells or AR positive stromal cells under androgen depleted condition. Upon stimulation with androgen in AR positive stromal cells, E2F1 is displaced from the binding site by AR and replaced with E2F4, leading to recruitment of the SMRT/HDAC3 co-repressor complex and repression of cyclin B1. Furthermore, the switch between E2F1 and E2F4 at the E2F binding site of the cyclin B1 promoter coincides with an androgen-dependent interaction between AR and E2F1 as well as cytoplasm to nucleus translocation of E2F4. In summary, our study revealed an association between distinct epithelial and stromal AR expression and PCa racial disparity as well as the molecular mechanism involved in regulating AR expression in epithelial and stromal prostate cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY09-02. doi:1538-7445.AM2012-SY09-02

P1-08-16: Benign Breast Disease (BBD) and Breast Cancer in African American Women.

Abstract African American (AA) women have higher mortality rates from breast cancer (BrCa) and are diagnosed at younger ages than their Caucasian counterparts. Women who have had a benign breast biopsy are at increased risk of the disease, although less is known about the risk of BrCa associated with benign breast disease in AA women. We examined 1428 breast biopsies from AA women which occurred from 1997–2000 and assessed various pathologic markers including: apocrine metaplasia, ductal hyperplasia including atypia, evidence of cysts, duct ectasia, fibrosis, intra-ductal papilloma, sclerosing adenosis, columnar alteration, and involution (atrophy). These women were followed for later BrCa through the Metropolitan Detroit Cancer Surveillance System, part of the Surveillance, Epidemiology and End Results (SEER) program through 2008. Women who developed BrCa were compared to those in the cohort who did not, and to other AA women with BrCa in the SEER registry. AA women in our study were also compared to Caucasian women in the Mayo Clinic cohort. Differences in variables were assessed by chi-squared tests and 95% confidence intervals. Of the 1428 biopsies, 52 (3.6%) subsequent incident breast cancers were reported in SEER. The mean age at diagnosis was 59, and the mean time from biopsy to BrCa diagnosis was 6.1 years. Individuals with atypical ductal hyperplasia at biopsy (n=37, 2.6%) were more likely to develop breast cancer (n=7, 13.5%, p<0.01). No other pathologic variables were associated with increased risk. Women in our cohort with breast cancer did not differ from AA in the SEER database with respect to age at diagnosis, stage at diagnosis, or receptor positivity. Compared to the Caucasian women in the Mayo Clinic BBD cohort, AA women in our study were younger at biopsy (p<0.01), but had similar percentages of involution and atypia (p=0.50 and 0.15, respectively). Our preliminary findings among a relatively small group of AA women with prior benign breast biopsies and incident breast cancers suggest that results from the Mayo Cohort study are likely to apply to AA populations. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-08-16.

Abstract A89: Examination of ancestral informative markers and self-reported race with tumor characteristics of breast cancer among black and white women

Abstract African American (AA) women have higher mortality from breast cancer (BC) compared to European American (EA) women. This may be due to the higher proportion of AA women with tumors that are diagnosed at advanced stage and are estrogen receptor negative (ER-) /progesterone receptor negative (PR-). Our study sought to determine whether self-reported race and percent African ancestry were associated with BC tumor characteristics. In a multi-center, population-based case-control study of BC, we determined percent African ancestry using ancestry informative markers (AIM) among women self-reporting as Black. While self-reported race was associated with several BC tumor characteristics, AIMs markers among AA women were not. Specifically, women self-reporting as Black were at a 30% reduction in ER+/PR+ tumors (95% CI: 0.6–0.9), a non-significant risk of ER-/PR-tumors (OR = 1.3 [95% CI: 0.9–1.7]), a 1.4-fold increased risk of regional/distant stage (95% CI: 1.1–1.7) and a 1.5-fold increased risk of high grade tumors (95% CI: 1.2–1.9) compared to EA women. Percent African ancestry was not associated with any BC tumor characteristics (OR=1.0 for ER+/PR+ [95% CI: 0.6–1.8], OR = 0.9 for ER-/PR-[95% CI: 0.5–1.6], OR = 1.3 for regional/distant stage [95% CI: 0.8–2.1], and OR=0.9 for high-grade tumors [95% CI: 0.6–1.4] comparing those with ≥95% African ancestry to those with <80% African ancestry). This analysis suggests that factors unrelated to AA women's genetic ancestry contribute to racial differences in BC tumor characteristics. Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A89.

Abstract B46: Investigating the role of β-arrestin-2 in prostate cancer disparity using a β-arrestin-2 deficient mouse model of prostate cancer

Abstract African American men are more likely to develop and die from prostate cancer than Caucasian American men. While a complex interaction of social, environmental, and biological factors is likely to blame, molecular mechanisms of prostate cancer disparity remain poorly understood. Elucidation of these mechanisms is critical if we are to achieve better treatment options and ultimately, patient survival for African American men. β-arrestin-2 was initially recognized for its role in G-protein coupled receptor desensitization. More recent studies have demonstrated that several pathways critical to prostate cancer progression converge at β-arrestin-2 including androgen metabolism, angiogenesis, and metastasis. Preliminary data in our lab shows that prostate cell lines derived from Caucasian American men express less -arrestin-2 than those from African American men. This study aims to test the hypothesis that loss of β-arrestin-2 expression in prostate tumors attenuates tumor progression. In order to study this, we have established a β-arrestin-2 deficient TRAMP mouse model. TRAMP+/β-arrestin-2 KO mice develop tumors that are smaller than those in TRAMP+/β-arrestin-2 WT mice at 6 months of age. Similar results were observed when orthotopic TRAMP-C1 tumors were established in C57BL/6 mice. β-arrestin-2 knockdown in these cells resulted in delayed tumor growth. Taken together these data support the idea that increased β-arrestin-2 expression correlates with enhanced tumor progression providing a possible biological mechanism of prostate cancer disparity. Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B46.

Abstract 1114: IGF-II regulates the expression of estrogen receptor beta 5: Role in the survival disparity between African-American and Caucasian women with breast cancer

Abstract African American (AA) women with breast cancer are more likely to be diagnosed at a more advanced stage of the disease, have a higher recurrence rate and a poorer prognosis than Caucasian (CA) women. African American women are more often diagnosed with high-grade breast tumors at an earlier age most of which are negative for the estrogen and progesterone receptors. These factors result in a higher mortality rate among AA patients. This survival disparity can be attributed to socieconomic status and other related factors, however there are biological factors that may also be involved. The insulin-like growth factor II (IGF-II) plays a crucial role in fetal and cancer development by signaling through the IGF-I receptor (IGF-IR), the insulin receptor (InsR) and crosstalk with the estrogen receptor alpha (ER-α). Compared to CA women, AA women have an increased level of proIGF-II expression in breast tissues and higher signaling activation through the IGF-1 and InsRs. Since the estrogen receptor beta (ER-β) is also expressed in a majority of breast cancers we propose that IGF-II may also activate the ER-β signaling pathway. ER-β has 5 isoforms of which ER-β5 is the most abundantly expressed among AA women with breast cancer and it is associated with a poor prognosis and decreased survival. Thus, our hypothesis is that IGF-II activation of the ER-β5 contributes to the survival disparity between AA women and CA women. To test this hypothesis we analyzed the expression of ER-β5 in AA and CA breast cancer cell lines by western blot, siRNA analysis and IGF-II stimulation. IGF-II not only modulated the phosphorylation of ER-β5, but it also promoted the translocation of ER-β5 to different organelles. Thus, we conclude that ER-β5 may contribute to the survival disparity among AA breast cancer patients since ER-β5 impairs the inhibitory effect of other ER-β isoforms. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1114. doi:10.1158/1538-7445.AM2011-1114