Abstract P5-07-08: Survival relevance of tamoxifen sensitivity-related microRNAs, miR-342 and miR-221/222, in breast cancer patients
Authors: Young JS , Kawaguchi T , Yan L , Qi Q , Liu S , Takabe K 
Published: February 2018

BACKGROUND: MicroRNAs (miRNAs) are small noncoding RNAs, which regulate the expression of target genes post-transcriptionally by RNA interference. They have emerged as one of the crucial regulators of cancer progression. Some miRNAs are reported to be related to the response of breast cancer to tamoxifen (TAM). In this study, we investigated whether the levels of TAM-resistant miRNA (miR-221/222) and TAM-sensitive miRNA (miR-342) translate to breast cancer patient survival, using multiple large databases.

MATERIALS AND METHODS: The Cancer Genome Atlas (TCGA; n=1049), Gene Expression Omnibus (GEO; GSE19536 n=96, GSE22220 n=210), and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC; n=2509) datasets were used and Gene Set Enrichment Analysis (GSEA) was performed.

RESULTS: MiR-342 was identified as a TAM-sensitive miRNA, and miR-221/222 were identified as TAM-resistant miRNAs by literature search. Patients with high expression of miR-342 were shown to have better survival in TCGA (OS, p=0.02; DFS, p=0.03, respectively) and in two other independent GEO cohorts (OS, p=0.02 and p=0.0007, respectively) as well as in the METABRIC cohort (OS, miR-342-3p, p=0.006; miR-342-5p, p=0.00009). By subtype analyses, high expression of miR-342 was significantly associated with better survival in ER-positive patients (p=0.04), but not in ER-negative or triple negative patients in the TCGA cohort. This association was not observed in the METABRIC cohort. Within TCGA cohort, expression of TAM-resistant miR-221/222 did not significantly impact survival. Unexpectedly, increased expression of miR-221 was shown to have increased overall survival in all patients (p=0.00904) as well as in ER-negative patients (p=0.0479) and non-triple negative patients (p=0.0106) within the METABRIC cohort. On the other hand, low expression of miR-222 was associated with increased survival of all patients (p=0.00802) as well as in non-triple negative patients (p=0.041). Lastly, GSEA demonstrated that lower miR-342 expression was significantly seen in TAM-resistant gene sets, and higher miR-342 expression was seen TAM-sensitive gene sets, but miR-221/222 did not show any significant enrichment with TAM-resistant or TAM-sensitive gene sets. Taken together with survival data, expression levels of miR-342 reflect its TAM-sensitivity related function, however, that of miR-221/222 reflect other functions in breast cancer patients.

CONCLUSION: For the first time, we used “big data” from the TCGA, GEO and METABRIC cohorts to analyze multiple miRNAs with respect to TAM sensitivities and its survival impact. We demonstrated that expression of miR-342 reflected the sensitivity of the cancer cells to TAM sensitivity, however, that of miR-221/222 reflected other functions in breast cancer patients.

Citation Format: Young JS, Kawaguchi T, Yan L, Qi Q, Liu S, Takabe K. Survival relevance of tamoxifen sensitivity-related microRNAs, miR-342 and miR-221/222, in breast cancer patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-07-08.