Abstract 4769: Identification of differentially expressed microRNAs in African American women with quadruple-negative breast cancer

Abstract

Purpose: Recently, we have demonstrated that triple-negative breast tumors (TNBC) that lack the expression of androgen receptor are quadruple-negative tumors (QNBC) and have increased aggressiveness. Additionally, we determined that this is due to a unique gene signature in the QNBC subtype. However, whether this gene signature is associated with a unique miRNA expression and differential in African American (AA) women compared to Caucasian (CA) women has not been determined. Therefore, the purpose of this study is to determine the miRNA expression in presence or absence of androgen receptor in both African American and Caucasian QNBC patients. Methods: miRNA level 3 sequencing files were originally downloaded on June 01 2016 from TCGA for 925 breast cancer patients. The miRNA sequence files (RPKM) and gene expression files (FPKM UQ) were obtained for normal and tumor samples for these patients. Median value of AR FPKM UQ was used as cut-off and divided patient group as AR(+ve/-ve). Log2 fold change values were calculated by comparing AR-negative and AR-positive patients. P-value was calculated using two-tail t-test. GSE19783 (mRNA, miRNA data) was also obtained and was used as validating dataset. Results: Out of 925 patients, 101 patients have TNBC. Among TNBC patients, 107 are QNBC and 8 patients are AR +ve TNBC. Reads per million for 1046 miRNAs were considered for this study.40 miRNAs showed differential expression in QNBC. (p-value and lt 0.05). All BC patients were organized based on race (CA/AA), stage (I/II/III, IV) and subtype (Luminal, Her2type, TNBC).We have found that hsa-mir-452 and hsa-mir-937 expression was high in AR-negative, hsa-mir-190b expression was low in AR -ve African American women. miRNAs expression was changed in QNBC and correlated to AR (hsa-mir-577, hsa-mir-135b and hsa-mir-18a). hsa-mir-375 expression was low in QNBC.hsa-mir-150, hsa-mir-181a-2, hsa-mir-500a, hsa-let-7d, hsa-mir-92a-1, hsa-mir-92a-2, hsa-mir-20a, hsa-mir-17, hsa-mir-30a, hsa-mir-210, hsa-mir-455, hsa-mir-130a are expression was changed in African American women with QNBC. Hsa-mir-3607 is low in African American women, irrespective of AR expression. These results are in process of validation using independent dataset. Discussion/Conclusion: Standard treatment of breast cancer relies on reliable assessment by IHC analysis of ER, PR, and HER2. Our results suggest that the heterogeneity of TNBC is at least partially associated with the presence or absence of AR expression, suggesting that QNBC should be considered as a clinically relevant breast cancer subtype. IHC analysis of AR appears to be a practical assay to determine the most aggressive TNBC subtypes and identifies tumors that could benefit from available targeted therapies. miRNA isoform or novel miRNA needs to be discovered to further investigate the gene regulation for QNBC patients. Citation Format: Anusha Angajala, Raymond Hughley, Windy DeanColomb, Shweta Tripathi, Ming Tan, Clayton Yates. Identification of differentially expressed microRNAs in African American women with quadruple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4769.

Translational Implications of Dysregulated Pathways and microRNA Regulation in Quadruple-Negative Breast Cancer

“…MiR-135b expression was strongly and positively correlated with a high proliferative index. A recent study of African American women with QNBC by Angajala et al identified differentially expressed miRNAs associated with the disease [ 59 ]. This study compared TCGA miRNA sequencing results from women with QNBC, AR+ TNBC, luminal and Her2+ breast cancers.…”

“…In analysis of the few published studies that identify differentially regulated miRNAs in QNBC versus AR+TNBC, regulation of PI3K/PTEN and Myc signaling, superoxide dismutase and cell-cycle checkpoint come into view as potential pathobiologically meaningful pathways that may be dysregulated by disease-specific miRNAs. The analysis of TNBC subtypes in African American women by Angajala et al identified differentially regulated miRNAs that regulate Myc, TP53 and PTEN [ 59 ]. The use or targeting of these miRNAs and targets may have promise as therapeutic approaches, and PI3K/Akt/mTOR and cell cycle regulators have been previously considered to be prospective therapies for QNBC [ 15 ].…”

Prevalence and Mortality of Triple-Negative Breast Cancer in West Africa: Biologic and Sociocultural Factors

“… 27 Significant differences in QNBC biology between WA and CA women have also been reported. For instance, Angajala et al 93 reported a lower expression of hsa-mir-190b among AA patients with QNBC. There are limited data on QNBC in WA as AR expression analysis is uncommon.…”