Outcome Disparities in African American Compared with European American Women with ER +HER 2- Tumors Treated within an Equal-Access Health Care System

Costantino, Nicholas S.; Freeman, Benjamin; Shriver, Craig D.; Ellsworth, Rachel E.

doi:10.18865/ed.26.3.407

Cited by 8 publications

(16 citation statements)

References 38 publications

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“…1e, adj p = 5.8E−04 and adj p = 1.9E−06, respectively; one-way ANOVA with Tukey HSD test). These data correspond with a subset of studies that suggest CRYβB2P1 , and not CRYβB2 , is the gene associated with health disparities and poor outcome in breast cancers [23, 24]. When evaluating the data by first conditioning based on either subtype or race, the same patterns of significance persisted for each gene with only one exception; CRYβB2 expression was no longer significantly higher in Her2 compared to luminal A tumors (Additional file 3: Figure S1A&B).…”

Section: Resultssupporting

confidence: 80%

A functional role for the cancer disparity-linked genes, CRYβB2 and CRYβB2P1, in the promotion of breast cancer

et al. 2019

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Background In the USA, the breast cancer mortality rate is 41% higher for African-American women than non-Hispanic White women. While numerous gene expression studies have classified biological features that vary by race and may contribute to poorer outcomes, few studies have experimentally tested these associations. CRYβB2 gene expression has drawn particular interest because of its association with overall survival and African-American ethnicity in multiple cancers. Several reports indicate that overexpression of the CRYβB2 pseudogene, CRYβB2P1, and not CRYβB2 is linked with race and poor outcome. It remains unclear whether either or both genes are linked to breast cancer outcomes. This study investigates CRYβB2 and CRYβB2P1 expression in human breast cancers and breast cancer cell line models, with the goal of elucidating the mechanistic contribution of CRYβB2 and CRYβB2P1 to racial disparities. Methods Custom scripts for CRYβB2 or CRYβB2P1 were generated and used to identify reads that uniquely aligned to either gene. Gene expression according to race and tumor subtype were assessed using all available TCGA breast cancer RNA sequencing alignment samples (n = 1221). In addition, triple-negative breast cancer models engineered to have each gene overexpressed or knocked out were developed and evaluated by in vitro, biochemical, and in vivo assays to identify biological functions. Results We provide evidence that CRYβB2P1 is expressed at higher levels in breast tumors compared to CRYβB2, but only CRYβB2P1 is significantly increased in African-American tumors relative to White American tumors. We show that independent of CRYβB2, CRYβB2P1 enhances tumorigenesis in vivo via promoting cell proliferation. Our data also reveal that CRYβB2P1 may function as a non-coding RNA to regulate CRYβB2 expression. A key observation is that the combined overexpression of both genes was found to suppress cell growth. CRYβB2 overexpression in triple-negative breast cancers increases invasive cellular behaviors, tumor growth, IL6 production, immune cell chemoattraction, and the expression of metastasis-associated genes. These data underscore that both CRYβB2 and CRYβB2P1 promote tumor growth, but their mechanisms for tumor promotion are likely distinct. Conclusions Our findings provide novel data emphasizing the need to distinguish and study the biological effects of both CRYβB2 and CRYβB2P1 as both genes independently promote tumor progression. Our data demonstrate novel molecular mechanisms of two understudied, disparity-linked molecules.

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Section: Resultssupporting

confidence: 80%

A functional role for the cancer disparity-linked genes, CRYβB2 and CRYβB2P1, in the promotion of breast cancer

et al. 2019

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“…Our systematic search clearly indicated that African-American populations, as well as Hispanics, were associated with a risk factor for developing particular forms of BC. ER + BC tends to be associated with Caucasian women, and triple-negative breast cancer tends to be associated with ethnicity/race [ 37 , 38 ]. MiR-34a is more accurate in a large cohort study of tissue-based IBC.…”

Section: Discussionmentioning

confidence: 99%

The diagnostic role of microRNA-34a in breast cancer: a systematic review and meta-analysis

et al. 2017

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BackgroundMicroRNA-34a (miR-34a) is a master regulator of tumor suppression in breast cancer (BC). This systematic review aims to analyze the diagnostic accuracy of miR-34a in the detection of BC as a biomarker.ResultsA total of 1858 BC cases and 494 controls from thirteen eligible studies reported in 9 publications were included. The overall pooled sensitivity, specificity, negative likelihood ratio (NLR), positive likelihood ratio (PLR), and diagnostic odds ratio (DOR) were 85.50% (95% CI: 83.80-87.00%), 70.00% (95% CI: 65.80–74.10%), 0.29 (95% CI: 0.19–0.43), 2.58 (95% CI: 1.91–3.43), and 9.39 (95% CI: 5.47–16.12), respectively. Similarly, the overall area under the curve (AUC) of the summary receiver operating characteristic (SROC) was 0.80, indicating the high conservation of miR-34a as a biomarker. Furthermore, subgroup analysis suggested that the use of miR-34a as a biomarker is more accurate in tissue-based sample of invasive BC. We also indicated that miR-34a is a capable biomarker in diagnosing BC in people of Caucasian descent.Materials and MethodsA systematic search was conducted for eligible publications that address miR-34a expression level in BC cases and noncancerous controls. Diagnostic capacity of miR-34a for BC was assessed using pooled sensitivity and specificity, DOR, and AUC of SROC. PLR and NLR were verified to estimate the miR-34a diagnostic accuracy in clinical level. The quality of the included studies was assessed by QUADAS-2.ConclusionsThese findings suggest miR-34a is a promising non-invasive biomarker in diagnosing BC. Well-designed cohort studies should be implemented to warrant the diagnostic value of miR-34a in clinical purposes.

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“…Tumor datasets: Our first dataset (GEO78958, Table S2 , referred to henceforth as dataset #1) had microarray data from 51 AA tumors with luminal (predominantly ER+) breast cancer, and 169 CA tumors 12 . Our second dataset (GSE18229, Table S3 ), referred to henceforth as dataset #2) had microarray gene expression data from 44 AA tumors and 85 CA tumors 25 .…”

Section: Methodsmentioning

confidence: 99%

“…Therefore, our results reflect the DDR landscape of CAs. Since AAs have worse outcomes than CAs 2,12,24 , we hypothesize that resistance to endocrine therapy associated with higher frequency of dysregulation of DDR genes contributes to this outcome disparity. This is an especially relevant hypothesis since DDR pathways are molecular liaisons between external stressors (e.g.…”

Section: Introductionmentioning

confidence: 99%

“…There is consensus in the literature that environmental/socioeconomic factors contribute to poor breast cancer outcome in AAs 5,6,10,11 . These include reproductive factors and socioeconomic factors including access to healthcare [12][13][14][15][16][17] . However, even when these factors are controlled for, differences in presentation and outcome persist in AA ER+ breast cancer patients 15 .…”

Section: Introductionmentioning

confidence: 99%

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Race specific differences in DNA damage repair dysregulation in breast cancer and association with outcome

Mazumder

Jimenez

Ellsworth

et al. 2020

Preprint

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IMPORTANCE: African American (AA) breast cancer patients have worse outcomes than Caucasian Americans (CAs). DNA damage repair (DDR) genes drive poor outcome in CA estrogen receptor (ER)+ breast cancer patients. Whether DDR genes similarly impact survival in AAs is unknown. Identifying AA-specific patterns of DDR dysregulation could change how we tailor predictive/prognostic biomarkers. OBJECTIVE: To characterize DDR dysregulation in ER+ AA patient tumors and test associations with clinical outcome. DESIGN SETTINGS AND PARTICIPANTS: Three independent tumor, and two normal breast datasets were analyzed. Tumor datasets: (1) GSE78958 (2) GSE18229 (3) The Cancer Genome Atlas (TCGA). Normal datasets: (4) GSE43973 (5) GSE50939. MAIN OUTCOME AND MEASURES: Up/down-regulation of 104 DDR genes was assessed in AA samples vs CAs. Survival associations were assessed for genes dysregulated in multiple datasets. RESULTS: Overall, RNA levels of single strand break repair (SSBR) genes were downregulated in AA tumors and double strand break repair (DSBR) genes were upregulated compared to CAs. While SSBR downregulation was mainly detected in tumors, DSBR upregulation was detectable in both tumor and normal breast AA samples. Seven specific DDR genes identified as dysregulated in AAs vs CAs in multiple datasets associated with poor survival. A subset of tumors with simultaneous dysregulation of homologous recombination and single strand break repair genes was enriched in AAs and had associated consistently with poor survival. CONCLUSION AND RELEVANCE: Overall, these results constitute the first systematic analysis of differences in DDR regulation in AA ER+ tumors and normal tissue vs CAs. We identify a profile of DDR dysregulation enriched in AA patients, which associates with poor outcome. These results suggest a distinct molecular mechanism of DDR regulation in AAs that lays the groundwork for refining biomarker profiles by race and improving precision medicine for underserved populations.

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Outcome Disparities in African American Compared with European American Women with ER +HER 2- Tumors Treated within an Equal-Access Health Care System

Cited by 8 publications

References 38 publications

A functional role for the cancer disparity-linked genes, CRYβB2 and CRYβB2P1, in the promotion of breast cancer

A functional role for the cancer disparity-linked genes, CRYβB2 and CRYβB2P1, in the promotion of breast cancer

The diagnostic role of microRNA-34a in breast cancer: a systematic review and meta-analysis

Race specific differences in DNA damage repair dysregulation in breast cancer and association with outcome

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