Abstract 1899: Let-7b overexpression is associated with higher nucleotide excision repair pathway in women with breast cancer

Abstract

Abstract Nucleotide Excision Repair (NER) is a critical pathway involved in breast cancer (BC). We have previously published that a low DNA repair capacity (DRC) is associated with a higher risk of BC in Puerto Rican women. In recent years we have focused our investigations on microRNAs (miRNAs) that are differentially associated with a low and a high DRC in women with BC and controls. A discovery experiment with 29 BC cases and 27 controls produced 12 candidate miRNAs associated with DRC including let-7b. The main objective of this study was to elucidate if there is a correlation between let-7b expression and specific DRC levels. Let-7b belongs to a miRNA family with tumor suppressor activity that targets oncogenic genes such as Ras, Myc, and HmgA2. DRC was measured in lymphocytes by means of a host cell reactivation assay with a luciferase reporter gene. We isolated miRNAs from plasma of 145 Puerto Rican women with and without BC (recently diagnosed, untreated cases and controls) using the miRNeasy kit (Qiagen). These women were divided into four groups according to their DRC level: high (>3.8%) and low (<3.8%). The four groups consisted in BC cases with high (n = 32) and low (n = 41) DRC, and controls with high (n = 38) and low (n = 34) DRC. Let-7b expression was measured using TaqMan microRNA assay. In addition, epidemiological data of these women has been collected at their initial BC diagnosis (before treatment) and almost five years after diagnosis. Within the BC group with low DRC, 9 women had presented recurrence. We found no significant difference in let-7b expression between controls without BC when compared to women with BC with both high and low DRC levels. A significant difference in let-7b expression was found in BC cases with high DRC when compared with the remaining groups (p<0.001). The down-regulation of let-7b family miRNAs is associated with poor prognosis in various types of cancers, including breast, lung, and ovarian, among others. Thus, our data reveal a possible role of let-7b involving DRC intrinsically when the malignancy is developed. Our findings support the association previously reported between a poor prognosis in several cancers and low levels of let-7b expression. Our study is innovative because it provides the first evidence that let-7b might play role in DRC (through the NER pathway) regulation in BC. Also, our study suggests that the overexpression of let7-b in women with BC and a high DRC is associated with a better prognosis. Supported by grants from the NCI Center to Reduce Health Disparities and NIH-NIGMS MBRS Program grants #S06 GM008239-20, 9SC1CA182846-04, GM082406, and PSM-MCC Partnership grant #5U54CA163071-04. Citation Format: Jarline Encarnacion, Carmen Ortiz, Ralphdy Vergne, Wanda Vargas, Jaime L. Matta. Let-7b overexpression is associated with higher nucleotide excision repair pathway in women with breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1899.