Abstract P3-10-04: microRNA-125a high expressing tumors enrich cell proliferation associated gene sets and associated with poor prognosis in estrogen receptor positive breast cancer patients
Authors: Tokumaru Yoshihisa , Futamura Manabu , Taniguchi Kohei , Oshi Masanori , Mase Junichi , Asano Yoshimi , Mori Ryutaro , Takabe Kazuaki , Yoshida Kazuhiro 
Published: March 2022

Abstract
Background: MicroRNA-125a (miR-125a) has been shown to function as tumor suppressive miRNA by pre-clinical in vitro studies. However, to the best of our knowledge, there is no study that investigated the clinical relevance of miR-125a in breast cancer patients. We hypothesized that miR-125a high expressing breast cancer associate with less aggressive cancer characteristics and with favorable survival outcome. Material and Methods: The clinicopathological and survival information associated with comprehensive transcriptomic data was analyzed in 2042 breast cancer patients from large publicly available databases, The Molecular Taxonomy of Breast Cancer International Consortium (METARBRIC) The Cancer Genome Atlas (TCGA), and GSE57897. The survival analysis, gene set enrichment analysis (GSEA) were conducted comparing miR-125a high expressing and low expressing tumors, divided by the median cutoff. The association between the miR-125a expression and tumor immune microenvironment was assessed by utilizing xCell. Results: The expression levels of miR-125a were lower in tumors compared with normal breast tissues in both TCGA and GSE57897 cohorts, which is in agreement with the notion that it is a tumor suppressive miRNA (p&lt;0.001 and p&lt;0.001, respectively). ER-positive/HER2-negative (ER+/HER2-) showed the highest miR-125a expression among the subtypes in TCGA (p&lt;0.001). MiR-125a expression was not associated with cancer staging in any of the subtypes in neither TCGA nor METABRIC cohorts. Surprisingly, miR-125a high expressing tumors demonstrated worse disease free (DFS), disease specific (DSS), and overall survival (OS) compared with low expressing in ER+/HER2- breast cancer patients (p=0.008, p=0.005, and p=0.037) which was not the case for the other subtypes in METABRIC cohort. Interestingly, we found that miR-125a expression significantly correlated with Nottingham histological grade only in ER+/HER2- among the subtypes (p&lt;0.001). miR-125a high tumors significantly demonstrated higher expression of MKI67, one of the most commonly used parameters for cell proliferation, correlated with miR-125a expression in ER+/HER2- and Her2-positive patients (both &lt; p=0.02), but not in triple negative breast cancer (TNBC). Furthermore, miR-125a high expressing tumors enriched four out of five cell proliferation related gene sets in Hallmark collection, such as E2F Targets, G2M Checkpoint, Mitotic Spindle, and MYC Targets V2 in ER+/HER2- subtype, but not in TNBC. This was also the case in immune-related gene sets; interferon-alpha response and interferon-gamma response that enriched to miR-125a high tumors in ER+/HER2-, but not in TNBC. Infiltration of CD8 cells, T-helper type 1 cells, T-helper type 2 cells and M1 macrophages were all elevated in MiR-125a high ER+/HER2- subtype (all p&lt;0.03), but none in TNBC. We found that tumor suppressive miR-125a was highly expressed in ER+/HER2- subtype, where its expression was associated with multiple clinical and molecular biological parameters of cell proliferation, as well as with both favorable and unfavorable immune response. Given its association with the survival outcome, we cannot help but speculate that miR-125a expression parallels with highly proliferative ER+/HER2- breast cancer, but its tumor suppressive effect is not enough to improve survival outcome. This study is hypothesis generating, and our results need mechanistic analyses by experimental investigations. Conclusion: MiR-125a high tumors were associated with aggressive characteristics in ER+/HER2- patients which may contribute to the worse survival outcomes. The current result support the importance of analyses of large patient cohorts to clarify the role of a miRNAs in patients.
Citation Format: Yoshihisa Tokumaru, Manabu Futamura, Kohei Taniguchi, Masanori Oshi, Junichi Mase, Yoshimi Asano, Ryutaro Mori, Kazuaki Takabe, Kazuhiro Yoshida. microRNA-125a high expressing tumors enrich cell proliferation associated gene sets and associated with poor prognosis in estrogen receptor positive breast cancer patients [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-10-04.