Differentially expressed miRNAs in triple negative breast cancer between African-American and non-Hispanic white women

Abstract

Triple Negative Breast Cancer (TNBC), a clinically aggressive subtype of breast cancer, disproportionately affects African American (AA) women when compared to non-Hispanic Whites (NHW). MiRNAs(miRNAs) play a critical role in these tumors, through the regulation of cancer driver genes. In this study, our goal was to characterize and compare the patterns of miRNA expression in TNBC of AA (n = 27) and NHW women (n = 30). A total of 256 miRNAs were differentially expressed between these groups, and distinct from the ones observed in their respective non-TNBC subtypes. Fifty-five of these miRNAs were mapped in cytobands carrying copy number alterations (CNAs); 26 of them presented expression levels concordant with the observed CNAs. Receiving operating characteristic (ROC) analysis showed a good power (AUC ≥ 0.80; 95% CI) for over 65% of the individual miRNAs and a high combined power with superior sensitivity and specificity (AUC = 0.88 (0.78−0.99); 95% CI) of the 26 miRNA panel in discriminating TNBC between these populations. Subsequent miRNA target analysis revealed their involvement in the interconnected PI3K/AKT, MAPK and insulin signaling pathways. Additionally, three miRNAs of this panel were associated with early age at diagnosis. Altogether, these findings indicated that there are different patterns of miRNA expression between TNBC of AA and NHW women and that their mapping in genomic regions with high levels of CNAs is not merely physical, but biologically relevant to the TNBC phenotype. Once validated in distinct cohorts of AA women, this panel can potentially represent their intrinsic TNBC genome signature.

The orphan nuclear receptor estrogen-related receptor beta (ERRβ) in triple-negative breast cancer

“…This 20patient subset included 6 TNBC patients and 14 NTN patients. Principal component analysis (PCA) of 3000 AIMs overlaid with self-reported ethnicity of our cases showed separation of distinct ancestral populations [22] when merged with two populations from the 1000 Genomes Project: African descent (AFR) and ad mixed American (AMR) (Fig. 3c).…”

“…Next, we sought to determine if the observed decrease in ESRRB mRNA expression found in TNBC/BLBC may be due to copy number loss. We approached this by analyzing an independent, 106-patient cohort of Caucasian (CW) and African American (AA) patients with TNBC and non TNBC (NTN) using array comparative genomic hybridization (aCGH) as previously described by Sugita, et al [22]. ESRRB copy number was calculated and defined as deletion, loss, gain, or amplification, and demographic information was analyzed for associations with ESRRB copy number changes ( Fig.…”

Patterns of copy number alterations in primary breast tumors of South African patients and their impact on functional cellular pathways

“…A genome-wide analysis of CNAs conducted in different types of cancer revealed that a specific tumor type presents 17% of regions with amplifications and 16% of deletions, compared with <0.5% in normal samples (40). The patterns of these somatic tumor alterations, as CNVs, may also vary within ethnic groups (35,41). The majority of the studies assessing these alterations, in addition to their gene and epigenetic expression profiles, are in White European and African American patients with breast cancer (35,(40)(41)(42)(43)(44)(45).…”

“…The patterns of these somatic tumor alterations, as CNVs, may also vary within ethnic groups (35,41). The majority of the studies assessing these alterations, in addition to their gene and epigenetic expression profiles, are in White European and African American patients with breast cancer (35,(40)(41)(42)(43)(44)(45). Few studies have been performed in patients from Sub-Saharan countries (24,25).…”

“…DNA was isolated using the standard phenol-chlorophorm method as was previously described (32). Normal (reference) DNA was prepared from the peripheral blood of a pool of multiple healthy female donors, as previously described (35,36). Equal amounts of tumor and reference genomic DNA (300-500 ng) were digested and enzymatically labeled using the SureTag Complete DNA Labeling kit (Agilent Technologies, Inc.) and hybridized to the arrays, according to the manufacture's protocols.…”