Caucasian American Women Research Articles

Abstract LB312: Subtype- and race-specific differences in immune landscape of breast cancer

Abstract Tumor mass comprises of not just the tumor cells but a variety of stromal cells. Immune cells residing within the tumor microenvironment modulate the growth and behavior of the tumor cells through a bi-directional crosstalk and affect the outcomes of cancer therapies. Breast cancer (BC) is a highly heterogeneous disease having four major molecular subtypes. Triple-negative breast cancer (TNBC) is the most aggressive subtype and has limited available therapeutic options. Further, it disproportionately affects African American (AA) women, with nearly two times higher incidence as compared to Caucasian American (CA) women. It is associated with an earlier onset and overall higher mortality of BC. Here, we investigated the differences in the immune landscape between TNBC and non-TNBC subtypes and examined if there existed any race-specific patterns. A total of 81 breast cancer samples with a distribution of 55 non-TNBC (28 CA and 27 AA) and 26 TNBC (12 CA and 14 AA) were selected after histopathologic analysis. Tissues were analysis using the NanoString nCounter® pancancer immune panel to determine tissue-specific immune cell populations. We observed a significantly higher presence of tumor-infiltrating lymphocytes in TNBC compared to non-TNBC, with a higher immune score for CD45+ (total lymphocytes), T-cells, B-cells and tumor-associated macrophages. Specifically, among the T-cell population, Treg cells, Th1 cells, and CD8+ cells were higher in TNBC samples. The pathway prediction indicated 'primary immunodeficiency' and 'cancer immunotherapy by PD-1 blockade' pathways being significantly up-regulated in TNBC samples. Overexpression of CTLA4, IDO1, PDL1 and PDL2 as well as Treg marker genes, such as FOXP3 and LAG3, which are involved in immunosuppressive pathways, was observed in TNBC. In race-wise comparisons of non-TNBC and TNBC sample between CA and AA patients, we found that AA non-TNBC tumors had higher Treg cell scores. On the other hand, CA TNBC samples had higher Th1 and CD8+ T-cell scores compared to AA TNBC. The pathway prediction from differentially expressed genes between CA and AA non-TNBC samples showed complement activation pathway to be down-regulated in AA patients, which could be associated with an increased presence of Treg cells. Further, when comparing CA vs AA TNBC samples, we found significant up-regulation of oncogene BMI1 and down-regulation of genes involved in T-cell activation such as CD47, CD44, FOS, and S100A8 in AA TNBC, supporting their more aggressive nature. In conclusion, our data show that TNBC patients have a higher infiltration of immune cells, which remain suppressed due to the presence of Treg cells and PD1 signaling pathway. The presence of higher Treg cells in AA non-TNBC and lower Th1 and CD8+ T-cells in AA TNBC samples suggests an overall immune suppressed microenvironment in AA patients compared to CA patients. Overall, our data suggest that TNBC could be good candidate for immune therapy. Citation Format: Amod Sharma, Kunwar Somesh Vikramdeo, Sarabjeet Kour Sudan, Mohammad Aslam Khan, Mohammad Tahir, James Elliot Carter, Cindy Nelson, Ajay P Singh, Seema Singh. Subtype- and race-specific differences in immune landscape of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB312.

Abstract 1014: Disparities of triple negative breast cancer in Mississippi

Abstract Background: Triple-negative breast cancer (TNBC) accounts for about 10-15% of all breast cancers nationwide with disparities of incidence and outcomes among races, geographic locations, and other factors. This study is aimed to analyze the differences in the rate of TNBC, patient conditions at time of diagnosis, and death from TNBC among women in Mississippi. Methods: A retrospective study was conducted to serially review breast cancer cases diagnosed in the University of Mississippi Medical Center during May 2016 to May 2023. The entire breast cancer population was then stratified by race. The rate of TNBC, age and BMI at time of diagnosis, the rate of expiration were compared between African American (AA) and Caucasian American (CA) women with breast cancer. Two-tailed Student’s T-test was used to calculate the difference in mean values, and Chi-Square Test was used to compare the difference in rates or percentages. The significant p value was set at p<0.05. Results: In total 291 women with breast cancer, AA patients were 195 (67.01%), CA patients were 88 (30.24%), and other were 8 (2.75%). The mean age of all patients was 58.3 years-old (ranged 24-97). The mean BMI was 31.19. The patients with TNBC were 109 (37.46%) in entire studied population. A total of 32 (1.6%) patients, including 14 TNBC and 18 non-TNBC were expired with an average age of 61.84 and an average survival time of 20 months from diagnosis to expiration. As compared to CA patient population, AA breast cancer patients had onset at younger age (58.08±0.88 vs. 59.18±1.36), had a higher BMI (31.79±0.62 vs. 28.25±1.05, p=0.017), higher percentage of TNBC (41.54% vs. 30.68%, p=0.082 and OR=1.605), and higher rate of expiration (11.28% vs, 9.1%). Also, as compared to CA expired patients with breast cancer, AA expired patients had higher BMI (29.57 vs. 28.61), shorter survival time (17.5 months vs. 19.4 months), and died at younger age (61.84-year old vs. 66.38-year old) with a higher proportion of TNBC subtype (54.6% vs 12.5%, p=0.045, OR=9.6). Conclusions: Breast cancer is greatly disparate racially between AA and CA and geographically between Mississippi and US national average. The disparities are manifested in the proportion of TNBC subtype, age at onset of breast cancer, BMI at time of diagnosis, and death rate. Citation Format: Navdeep Kaur, Javaria A. Khan, Jinghe Mao, Diva Melvin, Muhammad M. Hassan, Xinchun Zho. Disparities of triple negative breast cancer in Mississippi [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1014.

Abstract 504: Anticancer effects of kaempferol through cell cycle arrest and the inhibition of proliferation in genetically distinct triple-negative breast cancer cells

Abstract Triple-negative breast cancer (TNBC) is one of the most known aggressive subtypes of breast cancer, affecting 1 in 3 newly diagnosed cancers in women. TNBC affects African-American women disproportionally in comparison to Caucasian women. Due to the lack of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptors (HER-2), it poses direct challenges to the efficacy of standard hormonal therapies. The current TNBC treatments present higher toxicity and multiple side effects. An alternative would be using natural compounds that have emerged as potential anticancer agents. Kaempferol is a major flavonoid aglycone found in many fruits, vegetables, and herbs, including grapes, tomatoes, broccoli, tea, and ginkgo biloba leaves. In this study, we investigated the differential effect of kaempferol on cell toxicity, cell growth, and underlying mechanisms in inducing cell cycle arrest in genetically different TNBC cells from Caucasian (MDA-MB-231) and African American (MDA-MB- 468) women. Kaempferol significantly inhibited cell growth in both the cell lines with a more profound effect against MDA-MB-231 (IC50: 43.86 µM) compared to MDA-MB-468 cells (IC50: 53.47 µM). Also, kaempferol treatment induced cell cycle arrest at S-phase in both cancer cell subtypes. The MDA-MB-231 cells showed a kaempferol effect at lower concentrations (6.25µM and 12.5µM), while MDA-MB-468 cells showed the same effect at higher concentrations (25µM and 50µM). Kaempferol also modulated CDK gene expression associated with cell cycle progression in breast cancer cells. The inhibition at S-phase is important in cancer treatment because it targets the highly proliferative nature of cancer cells characterized by uncontrolled cell division. This study indicates that, by inducing cell cycle arrest at the S-phase, kaempferol may interfere with cancer cell growth and proliferation by inhibiting DNA replication, offering potential therapeutic benefits. This approach could reduce side effects and increase treatment efficacy, providing hope for more effective interventions in the fight against TNBC. Citation Format: Sukhmandeep Kaur, Patricia Mendonca, Karam F. A. Soliman. Anticancer effects of kaempferol through cell cycle arrest and the inhibition of proliferation in genetically distinct triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 504.

Lip color diversity: An intricate study.

Lip investigations and characterizations in the literature are less prevalent than for skin, particularly on the topic of color diversity. However, as the consumer demand increases for a nude lip makeup result, that is, shades close to the bare lip color, the identification and modification of lip color is essential for the cosmetic industry. The objective was to highlight lip color diversity among three ethnicities (Caucasian, African and Hispanic), through the use of a spectral color measurement device especially adapted to the lip area, and to consider lip color ethnic specificities and overlaps. The inferior natural lip color was measured with a full-face hyperspectral imaging system, SpectraFace (Newtone Technologies, Lyon, France), on 410 healthy women aged 19 to 68 (Caucasian French, Caucasian American, African American, and Hispanic American women). A hierarchical ascending classification, was deployed to determine clusters based on the lip colorimetric parameters along two strategies to identify the best statistical analysis to preserve the lip color diversity. Lip color is a continuous color space, with great intra-ethnic and inter-ethnic diversity, especially for African American women in terms of chroma and lightness. Among the two strategies of data analysis, our two-step statistical clustering analysis yielded 11 groups (i.e., 11 lip tones), revealing an accurate representation of the scope of diversity, but also of the overlaps. The 11 lip tones/colors could potentially serve as target shades for the development of a more diverse and inclusive range of lip cosmetics, such as nude lipsticks.

Forearm vascular conductance responses to rhythmic handgrip in young African American compared with Caucasian American women

Non-Hispanic African American (AA) individuals have a disproportionately high prevalence, and mortality rate of cardiovascular disease (CVD) compared to other populations. Previous studies have demonstrated that even young, healthy AA individuals have blunted flow-mediated dilation, attenuated vasodilatory responses to pharmacological infusions and rhythmic handgrip exercise (RHG), as well as higher arterial stiffness and exaggerated peripheral vasoconstriction to isometric handgrip exercise and other non-exercise-stimuli compared to Caucasian-American (CA) individuals. These studies indicate that vascular alterations occur early on in life of AA individuals, potentially contributing to elevated risk of CVD in this racial group. However, these racial disparities in vascular function have almost exclusively been studied in men. Herein, we tested the hypothesis that, similar to young AA men, young AA women will exhibit an attenuated increase in forearm blood flow (FBF) and forearm vascular conductance (FVC) during rhythmic handgrip exercise (RHG) compared to age-matched CA women. Forearm blood flow (FBF; duplex Doppler ultrasound) and mean arterial pressure (MAP; finger photoplethysmography) were measured in young CA (n = 5) and AA (n = 5) women during rhythmic handgrip exercise performed at three workloads (15%, 30%, and 45% of maximal voluntary contraction (MVC)). FVC was calculated as FBF/MAP. Baseline FBF (CA: 66.0 ± 12.8 and AA: 61.6 ± 12.2 ml/min; mean ± SD, p = 0.30); FVC (CA: 0.8 ± 0.2 and AA: 0.7 ± 0.2 ml/min/mmHg; p = 0.16), MAP (CA: 82 ± 11 and AA: 88 ± 4 mmHg; p = 0.28), and MVCs (CA: 50 ± 4 and AA: 52 ± 5 kg; p = 0.35) were similar between the groups. Both groups exhibited intensity-dependent increases in FBF and FVC; however, contrary to our hypothesis, there were no race difference (mixed-model two-way ANOVA; FVC: race effect p = 0.18, intensity effect p < 0.0001, interaction p = 0.48). For instance, in response to RHG at 45%, CA had 384 ± 112% increase in FBF from baseline and AA had 499 ± 153% increase. Increase in FVC from baseline was 198 ± 76% for CA women and 314 ± 151% for AA women. MAP did not differ between the groups (e.g., ΔMAP at 45%; CA: 13 ± 11 vs AA: 9 ± 5, p = 0.41). These preliminary data suggest that the hyperemic response to rhythmic handgrip exercise in young African American women are similar to age-matched Caucasian-American women. Supported byKinesiology and Health Education UT Austin Start-up Account 19-2635-91. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Rapid onset vasodilation in response to forearm muscle contraction in Hispanic American and Caucasian American Adults

Hispanic Americans (HA) are the fastest growing ethnic populations in the U.S., estimated to double in the next four decades. According to NHANES 2013-2016 data, prevalence of type 2 diabetes (T2D) is 15.1% in HA men and 14.1% in HA women, compared to 9.4 and 7.3% in non-Hispanic Caucasian American (CA) men and women, respectively. Even HA children have a 5-fold higher rate of T2D compared to their age-matched CA counterparts. Impaired vascular function is a hallmark of T2D however, limited number of studies have investigated the effect of ethnicity on vascular function at rest and during exercise. To our knowledge, only one study has reported a higher flow-mediated dilation at rest in healthy HA compared to CA adults. Hence, the purpose of this study was to investigate the rapid onset vasodilation in response to a single muscle contraction of the forearm at progressively increasing intensity (20, 40, and 60% of maximum voluntary contraction (MVC)) in young, healthy HA compared to age- and weight-matched CA individuals. A single muscle contraction model was chosen to isolate the robust local vasodilatory responsiveness of the vasculature without increases in sympathetic nerve activity or large hemodynamic changes. We hypothesized that HA would demonstrate an attenuated forearm vascular conductance (FVC) and forearm blood flow (FBF) in response to skeletal muscle contractions, compared to CA group. Young, healthy HA (n=4) and CA (n=4) adults performed skeletal muscle contractions at 20%, 40 % and 60% of their maximum voluntary contraction (MVC). To isolate the effect of mechanical compression during muscle contractions, FBF and FVC responses to a brachial cuff inflation were also measured. Heart rate (ECG), mean arterial pressure (MAP; finger photoplethysmography) and forearm blood flow (FBF; duplex Doppler ultrasound) were measured. FVC was calculated as FBF/MAP. Baseline FBF (CA: 115.21 ± 48.9 and HA: 68.89 ± 21.9 ml/min; p=0.27), MAP (CA: 82 ± 7.48 and HA: 81 ± 2.87 mmHg; p=0.77), FVC (p=0.15), and MVCs (CA: 67 ± 26.8 and HA: 70 ± 7.4 kg; p=0.82) were similar between the groups. Following single muscle contractions, both groups exhibited an intensity dependent increase in FVC and FBF, however, there was no difference between HA and CA groups. For instance, following muscle contraction at 40% MVC, peak FVC (%Δ) was 251% ± 46.35 in HA and 189% ± 34.98 in CA (race effect p = 0.23, time effect = 0.01, interaction p = 0.029). Similarly, peak %Δ FBF or %Δ FVC following 60% contractions were similar between the groups (FVC: 327% ± 84.36 in HA vs. 286% ± 74.45 in CA (race effect p=0.62, time effect p<0.01, interaction effect p=0.01)). Both groups exhibited a similar response to brachial cuff inflation for peak FVC (p=0.21) and peak FBF (p=0.30). Our preliminary findings indicate that HA have a preserved rapid onset vasodilation in response to a single forearm contraction when compared to CA adults. Supported by Kinesiology and Health Education UT Austin Start-up Account 19-2635-91 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Racial differences in RAD51 expression are regulated by miRNA-214-5P and its inhibition synergizes with olaparib in triple-negative breast cancer

BackgroundTriple-negative breast cancer (TNBC) affects young women and is the most aggressive subtype of breast cancer (BC). TNBCs disproportionally affect women of African-American (AA) descent compared to other ethnicities. We have identified DNA repair gene RAD51 as a poor prognosis marker in TNBC and its posttranscriptional regulation through microRNAs (miRNAs). This study aims to delineate the mechanisms leading to RAD51 upregulation and develop novel therapeutic combinations to effectively treat TNBCs and reduce disparity in clinical outcomes.MethodsAnalysis of TCGA data for BC cohorts using the UALCAN portal and PrognoScan identified the overexpression of RAD51 in TNBCs. miRNA sequencing identified significant downregulation of RAD51-targeting miRNAs miR-214-5P and miR-142-3P. RT-PCR assays were used to validate the levels of miRNAs and RAD51, and immunohistochemical and immunoblotting techniques were used similarly for RAD51 protein levels in TNBC tissues and cell lines. Luciferase assays were performed under the control of RAD51 3’-UTR to confirm that miR-214-5P regulates RAD51 expression. To examine the effect of miR-214-5P-mediated downregulation of RAD51 on homologous recombination (HR) in TNBC cells, Dr-GFP reporter assays were performed. To assess the levels of olaparib-induced DNA damage responses in miR-214-5P, transfected cells, immunoblots, and immunofluorescence assays were used. Furthermore, COMET assays were used to measure DNA lesions and colony assays were performed to assess the sensitivity of BRCA-proficient TNBC cells to olaparib.ResultsIn-silico analysis identified upregulation of RAD51 as a poor prognostic marker in TNBCs. miRNA-seq data showed significant downregulation of miR-214-5P and miR-142-3P in TNBC cell lines derived from AA women compared to Caucasian-American (CA) women. miR-214-5P mimics downregulated RAD51 expression and induces HR deficiency as measured by Dr-GFP assays in these cell lines. Based on these results, we designed a combination treatment of miR-214-5P and olaparib in HR-proficient AA TNBC cell lines using clonogenic survival assays. The combination of miR-214-5P and olaparib showed synergistic lethality compared to individual treatments in these cell lines.ConclusionsOur studies identified a novel epigenetic regulation of RAD51 in TNBCs by miR-214-5P suggesting a novel combination therapies involving miR-214-5P and olaparib to treat HR-proficient TNBCs and to reduce racial disparity in therapeutic outcomes.

Abstract C021: Fucoxanthin anti-tumor effects on the proliferation, angiogenesis, apoptosis, and migration of triple-negative breast cancer cells

Abstract Breast cancer is the most commonly occurring cancer in women worldwide and is the second most common cancer among women in the United States. Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer and accounts for about 10-15% of all breast cancers. TNBC is mainly found in Caucasian and African American women. The tumor microenvironment promotes tumor initiation and progression, preceding invasive metastasis, increased cell growth, and angiogenesis. Therefore, the inhibition of these processes may reduce breast cancer development. Several dietary natural products show the ability to ameliorate the aggressiveness of breast cancer, leading to the inhibition of proliferation and angiogenesis, induction of apoptosis, and reduction of breast cancer progression and tumor development. PURPOSE: In the current study, the pharmacological effect of the natural compound fucoxanthin, a xanthophyll subset of carotenoids in brown macroalgae, is investigated in genetically different MDA-MB-231 (Caucasian) and MDA-MB-468 (African American) TNBC cell lines. METHODS: Cytotoxic and cell growth assays, angiogenic arrays, RT-PCR, apoptotic, and migration assays were performed. RESULTS: Fucoxanthin (1.56 - 300 µM) decreased cell viability in a dose and time-response manner in both cell lines, showing a higher potency in MDA-MB-468 cells. Fucoxanthin presented anti-proliferative effects in lower concentrations in MDA-MB-468 compared to MDA-MB-231 cells after 48 h and 72 h. Angiogenesis studies showed that fucoxanthin (6.25 µM) downregulates VEGF-A and VEGF-C expression in TNF-α-stimulated (50 ng/ml) MDA-MB-231 cells, but not in MDA-MB-468 cells in the transcription and protein levels. Fucoxanthin induced apoptosis in MDA-MB-231 cells but did not affect MDA-MB-468 cells. Additionally, fucoxanthin inhibited migration and invasion in both cell lines, showing a higher percentage of the inhibition of migrated cells in MDA-MB-468 cells after 72 h. CONCLUSION: Fucoxanthin may be a promising candidate for breast cancer therapy by targeting VEGF-A, and VEGF-C, decreasing cell proliferation, inducing apoptosis, and inhibiting cell migration and invasion. Citation Format: Shade' Ahmed, Patricia Mendonca, Samia Messeha, Ramesh Badisa, Karam F. Soliman. Fucoxanthin anti-tumor effects on the proliferation, angiogenesis, apoptosis, and migration of triple-negative breast cancer cells [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C021.

Racial Disparities in Screening and Management of Anemia Among Pregnant Women

Background: Iron deficiency anemia (IDA) in pregnancy is common in the United States, with an overall prevalence of 18%. ACOG and CDC guidelines recommend screening for anemia be done at the first prenatal visit with a CBC. IDA in pregnancy is associated with several adverse fetal and maternal health outcomes, including pre-term birth and low birth weight. Studies are just beginning to emerge describing racial disparities associated with assessment and management of IDA in pregnancy. Our primary objective in this study is to investigate the screening practices for anemia in pregnant women at our institution. Further objectives include investigating potential racial disparities in screening practices and management for anemia in pregnant women. Methods: We performed a retrospective cohort study of all pregnant women, aged 13-50 years old, who delivered at the University of Michigan (UM) between July 2015 and January 2022, and who received prenatal care at UM beginning the first trimester of pregnancy. After IRB approval, data were collected from the UM electronic medical record, MiChart. Inclusion in the cohort was based on CPT codes for delivery; first trimester visit was defined based on calculation from last menstrual period to 13 weeks of gestation. We used a t-test to compare mean hemoglobin (Hgb) and mean corpuscular volume (MCV) in Caucasian and African American women. We defined anemia as Hgb <10.5 g/dL during any point in pregnancy. We used Chi-square analysis to compare the proportion of Caucasian and African American women screened for anemia with Hgb and screened for iron deficiency with ferritin and transferrin saturation. Chi-square analysis was also used to compare the proportion of women prescribed iron supplementation. Results: A total of 16,073 pregnant women were included in the study, with 1,781 (11.08%) self-reported African Americans, 11,590 (72.11%) Caucasians, 1,472 (9.16%) Asians, and 1,230 (7.65%) women of other races/unknown. While screening for anemia was very common in our cohort, Caucasian women were slightly more likely to be screened for anemia than African American women (98.88% vs. 97.47%, p <0.001); see Table 1 below. Overall, 23.87% of women in our cohort were anemic at some point during pregnancy. Anemia was more common among African American women compared to Caucasian women (39.79% vs 21.41%, p <0.001). The mean Hgb was significantly higher in Caucasians versus African Americans (11.63 g/dL, SD 1.58 vs. 10.84 g/dL, SD 1.62, p <0.001). Mean MCV was lower in African Americans than Caucasians (85.94 fL, SD 6.63 vs. 89.04 fL, SD 5.12, p <0.001). African American women were more likely to be tested for iron deficiency compared to Caucasian women using ferritin (1.12% vs. 0.53%, p <0.001), and transferrin saturation (1.12% vs 0.44%, p <0.001). In terms of anemia management, 31.05% of patients overall were prescribed iron supplementation (oral or IV forms). African American women were more likely to be prescribed supplemental iron compared to Caucasian women (45.65% vs. 28.81%, p <0.001). Conclusion: Overall screening for anemia among pregnant women is very common among patients in our cohort, in congruence with guideline recommendations. Even though only a small proportion of patients did not have a Hgb checked during pregnancy, African American women were less likely to be screened for anemia during pregnancy compared to Caucasian women. In our cohort, pregnant African American women were more likely to be anemic, with a lower mean Hgb level and MCV compared to Caucasian women. Interestingly, although approximately one in four women were found to be anemic overall, less than 1% of women in our cohort had laboratory testing with ferritin or transferrin saturation to further work up iron deficiency. Despite this, nearly one third of patients received a prescription for iron supplementation. This suggests a frequent practice at our institution of empirically prescribing iron supplementation in the absence of laboratory work up for iron deficiency, especially among African Americans. Next steps include further evaluation as to whether this is an effective approach to treating anemia in pregnancy, or whether additional anemia work up is warranted in this population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Body fat percentage assessment using skinfold thickness agrees with measures obtained by DXA scan in African American and Caucasian American women

Dual-energy x-ray absorptiometry (DXA) is considered to have high accuracy in estimating fat mass; however, DXA is not always available. We hypothesized that the equations most commonly used for predicting body fat percentage (BF%) using skinfold thickness agree with direct measures of BF% obtained by DXA scan in African American (AA) and Caucasian American (CA) women. Data from 42 women from Alabama who were 21 to 45 years of age, who self-identify as AA (n=20) or CA (n=22) were included. BF% was estimated using DXA scan and through 6 different skinfold thickness equations. Agreement between DXA-BF% and BF% based on the skinfold thickness equations was assessed following the Bland-Altman method (bias and agreement limits). Agreement analysis showed in both AA and CA women that the BF%-Siri equation reflects better agreement and lower mean differences (bias) with BF%-DXA than the BF%-Brozek equation after applying 4 body density (BD) equations. Limits showed that BF%-Siri and BF%-Brozek predictive equations overestimate BF% compared with DXA-BF% in both AA and CA women. In AAs, equations that overestimated less were Wilmore and Behnke-Siri (by 1.81%) and Durnin and Womersley-Siri (by 2.5%) equations. Regarding CAs, equations that overestimated less were Durnin and Womersley-Siri (by 2.74%) and Wilmore and Behnke-Siri (by 3.11%) equations. The results of this study show that the BF%-Siri equation is a more accurate alternative than the BF%-Brozek equation for the calculation of BF%. In the calculation of BD, the Wilmore and Behnke equation in AA women and Durnin and Womersley in CA women were those that overestimated BF% to a lesser degree.

CmP signaling network unveils novel biomarkers for triple negative breast cancer in African American women.

Breast cancer is the most diagnosed cancer worldwide and remains the second leading cause of cancer death. While breast cancer mortality has steadily declined over the past decades through medical advances, an alarming disparity in breast cancer mortality has emerged between African American women (AAW) and Caucasian American women (CAW). New evidence suggests more aggressive behavior of triple-negative breast cancer (TNBC) in AAW may contribute to racial differences in tumor biology and mortality. Progesterone (PRG) can exert its cellular effects through either its classic, non-classic, or combined responses through binding to either classic nuclear PRG receptors (nPRs) or non-classic membrane PRG receptors (mPRs), warranting both pathways equally important in PRG-mediated signaling. In our previous report, we demonstrated that the CCM signaling complex (CSC) consisting of CCM1, CCM2, and CCM3 can couple both nPRs and mPRs signaling cascades to form a CSC-mPRs-PRG-nPRs (CmPn) signaling network in nPR positive(+) breast cancer cells. In this report, we furthered our research by establishing the CSC-mPRs-PRG (CmP) signaling network in nPR(-) breast cancer cells, demonstrating that a common core mechanism exists, regardless of nPR(+⁣/⁣-) status. This is the first report stating that inducible expression patterns exist between CCMs and major mPRs in TNBC cells. Furthermore, we firstly show mPRs in TNBC cells are localized in the nucleus and participate in nucleocytoplasmic shuttling in a coordinately synchronized fashion with CCMs under steroid actions, following the same cellular distribution as other well-defined steroid hormone receptors. Finally, for the first time, we deconvoluted the CmP signalosome by using systems biology and TNBC clinical data, which helped us understand key factors within the CmP network and identify 6 specific biomarkers with potential clinical applications associated with AAW-TNBC tumorigenesis. These novel biomarkers could have immediate clinical implications to dramatically improve health disparities among AAW-TNBCs.

Abstract 2212: Racially disparate serum levels of inflammatory cytokines, satiety and stress hormones, and exosomal microRNAs in women with or without a breast cancer diagnosis

Abstract Breast cancer (BC) is the most common non-cutaneous malignancy and the second leading cause of cancer-related death in American women. Health disparities in incidence and clinical outcome are also reported among different racial groups, most notably African American (AA) women, who are often diagnosed at a young age with aggressive BC and exhibit greater mortality than Caucasian American (CA) women. Since socioeconomic difficulties can have tremendous impact on psychophysiology besides limiting the access to optimal healthcare, we examined the serum levels of stress (cortisol) and satiety (leptin) hormones as well as inflammatory cytokines (resistin and interleukin-6/IL-6) in AA and CA women. To observe a potential epigenomic connection, we also performed profiling of a targeted set of exosomal microRNAs in serum samples. The study was conducted under an Institutional Review Board (IRB) approved protocol. All subjects participated voluntarily, and their consents were obtained. Serum levels of resistin, IL-6, leptin, and cortisol were quantified by Enzyme linked Immunosorbent Assay (ELISA) using commercial kits. Exosomes were isolated using precipitation method and recovered by standard centrifugation. Total RNA was isolated from exosomal preps and subjected to stem-loop RT-PCR for quantitation of a set of inflammation-associated microRNAs. We found that the levels of resistin, leptin, IL-6 and cortisol were higher in women with a BC diagnosis than non-BC subjects. Moreover, AA women with or without BC showed significantly higher levels of these cytokines and hormones in their serum as compared to the CA women with or without a BC diagnosis, respectively. We also observed differential expression of several microRNAs in serum of BC women as compared to their normal counterparts, of which five (miR511, miR33a, miR27a, miR6794, miR143-3p) exhibited highest presence in serum exosomes of AA women with BC. Together, these findings suggest that relatively greater exposure of minority women to social stressors may have epigenomic consequences and may potentially be linked to the observed BC racial health disparities. Citation Format: Sarabjeet Kour Sudan, Kunwar Somesh Vikramdeo, Amod Sharma, Sachin Kumar Deshmukh, Sanjeev Kumar Srivastava, Teja Poosarla, Nicolette P. Holliday, Donna L. Dyess, Ajay P. Singh, Seema Singh. Racially disparate serum levels of inflammatory cytokines, satiety and stress hormones, and exosomal microRNAs in women with or without a breast cancer diagnosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2212.

Lipidomics identifies novel circulating markers of CVD risk in African American and Caucasian women

Cardiovascular disease (CVD) is the leading cause of mortality for women in the USA. Women with dyslipidemia have at increased risk of CVD. The parameters of dyslipidemia have primarily been defined using Caucasian male populations. Current lipid markers of dyslipidemia such as high density lipoprotein (HDL), low density lipoprotein (LDL), and triglycerides have been shown to be poor predictors of CVD risk in African American populations. We aim to identify marks of dyslipidemia in African American populations that better predict risk and development of CVD.Untargeted lipidomics (total lipid #) was performed on sera from middle‐age African American and Caucasian women (n=872). Machine learning was used to identify predictive lipid markers of CVD risk. Findings were validated using an independent cohort of women (n=200).We identified unique and shared signatures of CVD in women based on race. Arachidonic acid containing lipids are positively correlated with elevated blood pressure and cardiomyopathy. Because these lipids are important in inflammatory signaling, we also assessed interleukin‐6 and c‐reactive protein. Through machine learning we were able to determine that markers of inflammation and inflammatory lipids were predictive of CVD in both Caucasian and African American women. Next, we will perform targeted lipidomics on these lipids of interest.Regardless of class, lipid species containing arachidonic acid were increased in circulation of women with hypertension. We propose the consideration of an inflammatory marker panel that includes arachidonic acid to assess CVD risk in women.

CmP Signaling Network Leads to Identification of Prognostic Biomarkers for Triple-Negative Breast Cancer in Caucasian Women.

Objective: Triple-negative breast cancer (TNBC) constitutes ∼15% of all diagnosed invasive breast cancer cases with limited options for treatment since immunotherapies that target ER, PR, and HER2 receptors are ineffective. Progesterone (PRG) can induce its effects through either classic, nonclassic, or combined responses by binding to classic nuclear PRG receptors (nPRs) or nonclassic membrane PRG receptors (mPRs). Under PRG-induced actions, we previously demonstrated that the CCM signaling complex (CSC) can couple both nPRs and mPRs into a CmPn signaling network, which plays an important role during nPR(+) breast cancer tumorigenesis. We recently defined the novel CmP signaling network in African American women (AAW)-derived TNBC cells, which overlapped with our previously defined CmPn network in nPR(+) breast cancer cells. Methods: Under mPR-specific steroid actions, we measured alterations to key tumorigenic pathways in Caucasian American women (CAW)- derived TNBC cells, with RNAseq/proteomic and systems biology approaches. Exemption from ethics approval from IRB: This study only utilized cultured NBC cell lines with publicly available TNBC clinical data sets. Results: Our results demonstrated that TNBCs in CAW share similar altered signaling pathways, as TNBCs in AAW, under mPR-specific steroid actions, demonstrating the overall aggressive nature of TNBCs, regardless of racial differences. Furthermore, in this report, we have deconvoluted the CmP signalosome, using systems biology approaches and CAW-TNBC clinical data, to identify 21 new CAW-TNBC-specific prognostic biomarkers that reinforce the definitive role of CSC and mPR signaling during CAW-TNBC tumorigenesis. Conclusion: This new set of potential prognostic biomarkers may revolutionize molecular mechanisms and currently known concepts of tumorigenesis in CAW-TNBCs, leading to hopeful new therapeutic strategies.

"You are the problem, not me": Personality Disorders in Later Life

Personality is defined by the unigue set of attributes, qualities and characteristics that shape how we cope with our lives. These emotional patterns, degree of reactivity and common behaviors define us over our lifespan. While a great deal of personality style is attributed to inherited traits; environmental and cultural influences clearly shape how we cope with life stressors and manage interpersonal relationships over time. Personality disorders emerge in early adulthood and persist into later life. Older adults who present with chronic and maladaptive patterns of coping pose unique challenges across a variety of clinical settings. The prevalence of these disorders in late life ranges from 5% to 13%, indicating that most clinicians will encounter these patients on a daily basis.The limited attention to cultural norms in the assessment and diagnosis of personality disorders is of significant concern. Available studies show trends in diagnosis related to culture and ethnicity such as a higher rate of Histrionic Persoanlity Disorder found among Latinx men compared to African American and Caucasian males. In addition a greater rate of Borderline Personality Disorder among Caucasian and African American women was found compared to Asian females. Woman in most culutral groups are more likley than men to be diagnosed with Dependent Personality Disorder. It is suggested that language issues and the interpretation of culturally appropriate behaviors may paly a role in diagnostic assessment drift and bias. The bias has a great impact in how we address clinical and treatment needs.The goal of treatment of personality disorders in late life is to decrease the intensity and frequency of disturbing symptoms and disruptive behaviors while trying to promote comfort and quality of life. This symposium will feature clinical case vignettes of older adults across a variety of backgrounds with features of personality disorders who have engaged in care in a large urban tertiary care program that serves a multicultural and socioeconomically diverse population. Issues faced by these patients over time include being labeled as "difficult," "needy," high maintenance," and "rejecting," with frequent switches in providers and lapses in care. The range of personality types and symptoms treated included avoidant, antisocial, borderline, histrionic, dependent, passive aggressive, narcissistic, paranoid and schizotypal. Sympotms were often mixed accross personality types and at times limited to one area. Individual treatment approaches for each patient were developed based on distressing symptoms, types of cluster traits and rational use of medication therapies with psychotherapuetic interventions lead to overall improvment in satifaction with care.In this session Dr. Kecia-Ann Blissett will present an overview of case vignettes to illustrate assessment, diagnosis and therapuetic treatment strategies. Dr. Melinda S Lantz will describe the barriers to treatment that older adults face focusing on access to care, cultural bias and the stigma facing oder adults who are labeled as difficult. Dr. Nikhil Tondehal will address the approach to culturally sensitive assessment and diagnosis of personality disorders in late life, focusing on attention to normative behaviors and coping skills accross ethnic backgrounds and cultures.

Abstract PO-101: CmP signaling network unveils novel biomarkers for triple negative breast cancer in African American women

Abstract Breast cancer is the most commonly diagnosed cancer worldwide and remains the second leading cause of cancer death. While breast cancer mortality has steadily declined over the past decades through medical advances, an alarming disparity in breast cancer mortality has emerged between African American women (AAW) and Caucasian American women (CAW); and new evidence suggests more aggressive behavior of triple-negative breast cancer (TNBC) in AAW may contribute to racial differences in tumor biology and mortality. Progesterone (PRG) is capable of exerting its cellular effects through either its classic, non-classic or combined responses through binding to either classic nuclear PRG receptors (nPRs) or non-classic membrane PRG receptors (mPRs), warranting both pathways an equally important status in PRG-mediated signaling. In our previous report, we demonstrated that the CCM signaling complex (CSC) consisting of CCM1, CCM2, and CCM3 proteins can couple both nPRs and mPRs signaling cascades to form a CSC-mPRs-PRG-nPRs (CmPn) signaling network in nPR positive(+) breast cancer cells. In this report, we furthered our research by establishing the CSC-mPRs-PRG (CmP) signaling network in nPR(-) breast cancer cells, demonstrating that a common core mechanism exists, regardless of nPR(+/-) cell type. This is the first report stating that inducible expression patterns exist between CCMs and major mPRs in TNBC cells. Furthermore, we firstly show mPRs in TNBC cells are localized in the nucleus and participate in nucleocytoplasmic shuttling in a coordinately synchronized fashion with CCM proteins under steroid actions, following the same cellular distribution as other well-defined steroid hormone receptors. Finally, for the first time, we deconvoluted the CmP signalosome by using multi-omics approaches, which helped us understand key factors within the CmP network, and identify 21 specific biomarkers with potential clinical applications associated with AAW-TNBC tumorigenesis. These novel biomarkers could have immediate clinical implications to dramatically improve health disparities among AAW-TNBCs. Citation Format: Johnathan Abou-Fadel, Jun Zhang. CmP signaling network unveils novel biomarkers for triple negative breast cancer in African American women [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-101.

YB1 Is a Major Contributor to Health Disparities in Triple Negative Breast Cancer.

Simple SummaryTriple negative breast cancer (TNBC) is a devastating disease that affects many women, due to the lack of FDA-approved targeted therapy. In the absence of cell surface receptors ER, PR, and Her2 that can be targeted with hormonal and antibody treatments, cytotoxic chemotherapy remains the major course of treatment, with a dismal response and rapid recurrence due to the acquisition of resistance. TNBC is also twice as more prevalent in African American (AA) when compared to Caucasian American (CA) women. This study investigated the role of the YB1 gene in the disparities in TNBC between AA and CA women. We found that YB1 is highly expressed in TNBC tumors of AA origin when compared to CAs. Increased expression levels and activity of YB1 correlates with poor disease outcomes, resistance to chemotherapy, and the activation of the cancer stem cell (CSC) phenotype, with higher levels in AA than in CA TNBC tumors. More importantly, we found that the targeted inhibition of the expression and activity of YB1 significantly inhibited the oncogenic behavior of AA tumors through sensitization to chemotherapy and inhibition of CSCs. Our study is the first to show that YB1 activity may be a major biological contributor to the health disparities in TNBC, and that development of therapies that specifically target YB1 could reduce these disparities.Triple negative breast cancer (TNBC) is the most aggressive amongst all breast cancer (BC) subtypes. While TNBC tumors represent less than 20% of all BC subtypes, they are responsible for the most BC-related deaths. More significantly, when considering TNBC incidence across all racial/ethnic groups, TNBC accounts for less than 20% of all BCs. However, in non-Hispanic black women, the incidence rate of TNBC is more than 40%, which may be a contributing factor to the higher BC-related death rate in this population. These disparities remain strong even after accounting for differences in socioeconomic status, healthcare access, and lifestyle factors. Increased evidence now points to biological mechanisms that are intrinsic to the tumor that contribute to disparate TNBC disease burdens. Here, we show that YB1, a multifunction gene, plays a major role in the TNBC disparities between African American (AA) and Caucasian American (CA) women. We show in three independent TNBC tumors cohorts, that YB1 is significantly highly expressed in AA TNBC tumors when compared to CAs, and that increased levels of YB1 correlate with poor survival of AA patients with TNBC. We used a combination of genetic manipulation of YB1 and chemotherapy treatment, both in vitro and in animal models of TNBC to show that YB1 oncogenic activity is more enhanced in TNBC cell lines of AA origin, by increasing their tumorigenic and aggressive behaviors, trough the activation of cancer stem cell phenotype and resistance to chemotherapeutic treatments.

Ancestry-Specific Interactions Between Circulatory Folate and One-Carbon Metabolism Genes’ Haplotypes for Higher-Grade Cervical Intraepithelial Neoplasia

Abstract Objectives Determine ancestry-specific interactions between circulatory folate concentrations, haplotypes of the one-carbon (1C) pathway genes and risk of higher-grade cervical intraepithelial neoplasia (CIN2+) in the US post-folic acid fortification era. Methods Study included self-reported African American and Caucasian American women positive for high-risk human papillomavirus (HPV) genotypes and diagnosed with ≤ CIN1 (non-cases, n = 340) or CIN2+ (cases, n = 337). Plasma and red blood cell (RBC) folate, vitamins B12 (B12) and C, and total carotene levels were measured. 660 single nucleotide polymorphisms of the 1C pathway genes and 104 ancestry informative markers (AIMs) were analyzed using buffy coat DNA and customizable Illumina GoldenGate arrays. Global African ancestry (GA) was estimated using the AIMs. Ancestry-based African American (AFR) had GA ≥ 0.8 and European Americans (EA) otherwise. Common haplotype blocks (n = 50) were tested for interactions with circulatory folate using logistic regression adjusting for age, education, body mass index (BMI), body fat %, smoking, parity, hormonal contraception use, plasma total carotene, B12 and C. False discovery rate &amp;lt; 0.1 was considered significant. Results Some of the main findings were, increasing plasma folate (1 SD) decreases the risk of CIN2 + when homozygous for haplotype CG at (rs575425, rs586199) of BHMT gene in EA (odds ratio/OR = 0.13, CI = 0.04,0.44), and for haplotype TA at (rs559062, rs515064) of CTH in AFR (OR = 0.23, CI = 0.1,0.52); increasing RBC folate (1 SD) decreases risk of CIN2 + when homozygous for haplotypes TA at (rs559062, rs515064) of CTH (OR = 0.27, CI = 0.12,0.61), AC at (rs7706298, rs10512934) of MTRR (OR = 0.21, CI = 0.08,0.57), and AGA at (rs11672909, rs759920, rs7253062) of DNMT1 (OR = 0.4, CI = 0.18,0.90) in AFR; and increasing RBC folate (1 SD) increases the risk of CIN2 + when homozygous for haplotypes GG at (rs3856027, rs4650051) of CTH gene (OR = 3.52, CI = 1.27,9.71), and CGG at (rs11672909, rs759920, rs7253062) of DNMT1 (OR = 5.70, CI = 1.86,17.49) in AFR. Conclusions Circulatory folate differentially modulates the risk for CIN2 + by interacting with haplotypes of the 1C pathway genes according to ancestry in reproductive-aged women exposed to US folic acid fortification program. Funding Sources National Cancer Institute

Computational features of TIL architecture are differentially prognostic of uterine cancer between African and Caucasian American women.

5585 Background: Although the vast majority of endometrial cancer (EC) is early-stage and thus, curable by surgery, chemotherapy, and radiotherapy (with at least 85% 5-year OS), a fraction of them are aggressive neoplasms such as high-grade or deeply invasive lesions and thus exhibit poor prognosis. African American (AA) women are disproportionately affected by high-grade EC and have 80% higher mortality rate compared with Caucasian American (CA) women. In this work, we evaluated the prognostic ability of computational measurements of architecture of tumor-infiltrating lymphocytes (ArcTIL) from H&amp;E slide images for EC. We also investigated the presence of morphologic differences in terms of ArcTIL features between AA and CA women and whether ArcTIL based population-specific models were more prognostic of OS in AA women compared to a population-agnostic model. Methods: The study included digitized H&amp;E tissue slides from 445 post-surgery EC patients from TCGA, with further chemotherapy, or radiotherapy, including only the AA and CA patients, patients without reported race or from other populations were excluded. The dataset was divided into discovery (D1, n = 300), and a validation set (D2, n = 145), while ensuring population balance between two splits (D1(AA) = 65, D1(CA) = 235, D2(AA) = 37, D2(CA) = 108). A machine learning approach was employed to identify tumor regions, and tumor-associated stroma on the diagnostic slides and then used to automatically identify TILs within these compartments. Graph network theory based computational algorithms were used to capture 85 quantitative descriptors of the architectural patterns of intratumoral and stromal TILs. A multivariable Cox regression model (MCRM) was used to create population specific-prognostic models (MAA, MCA) and a population-agnostic model (MAA+CA)) to predict OS. All 3 models were evaluated on D2(AA), D2(CA), and D2. Results: MAA identified 4 prognostic features relating to interaction of TIL clusters with cancer nuclei in stromal compartment and was prognostic of OS on D2(AA) (see Table) but not prognostic in D2(CA) nor D2(AA+CA). MCA and MAA+CA identified respectively 7 and 6 prognostic features relating to interaction of TIL clusters with cancer nuclei (both in the epithelial and stromal regions) and were prognostic of OS on D2(CA) and D2, but not prognostic in D2(AA). Conclusions: Our findings suggest an important role of stromal TIL architecture in prognosticating OS in AA women with EC, while epithelial TIL features were more prognostic in CA women. These findings need to be validated in larger, multi-site validation sets.[Table: see text]

Racial differences in dietary choices and their relationship to inflammatory potential in childbearing age women at risk for exposure to COVID-19

Since the ongoing coronavirus disease 2019 (COVID-19) pandemic is linked to chronic inflammation, people with initial lower inflammatory status could have better outcomes from exposure to this disease. Because dietary habits are one of the most important modifiable risk factors for inflammation, identification of dietary components associated with inflammation could play a significant role in controlling or reducing the risk of COVID-19. We investigated the inflammatory potential of diets consumed by African American (AA) and Caucasian American (CA) women of childbearing age (n = 509) who are at high risk for exposure to COVID-19 by being residents of Birmingham, Alabama, a city severely affected by this pandemic. The overall pro- and anti- inflammatory scores were calculated using dietary intake data gathered using Block food frequency questionnaire. The proinflammatory potential of diets consumed by AAs was significantly higher compared to CAs. Several anti- and proinflammatory nutrients and food groups consumed differed by race. With consumption of a greater number of antioxidants and B-vitamins, CAs switched toward an anti-inflammatory score more effectively than AAs while AAs performed better than CAs in improving the anti-inflammatory score with the consumption of a greater number of minerals and vitamin D. Effective race-specific dietary modifications or supplementation with nutrients identified will be useful to improve proinflammatory diets toward anti-inflammatory. This approach could aid in controlling the current COVID-19 pandemic and future pandemics of a similar nature in women at risk for exposure.