MicroRNA-382-5p aggravates breast cancer progression by regulating the RERG/Ras/ERK signaling axis

// Jar-Yi Ho 1, * , Ren-Jun Hsu 1, 2, 3, * , Jui-Ming Liu 4 , Szu-Chi Chen 1 , Guo-Shiou Liao 5 , Hong-Wei Gao 1 , Cheng-Ping Yu 1, 2, 3 1 Department of Pathology, and Graduate Institute of Pathology and Parasitology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan 2 Biobank Management Center of Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan 3 Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan 4 Division of Urology, Department of Surgery, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan 5 Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan * These authors have contributed equally to this work Correspondence to: Cheng-Ping Yu, email: cpyupath@yahoo.com.tw Keywords: miR-382-5p, RERG, Ras/ERK pathway, breast cancer Received: March 29, 2016 Accepted: September 20, 2016 Published: September 29, 2016 ABSTRACT Aberrant activation of the Ras/ERK pathway mediates breast cancer initiation and aggressiveness. Therefore, it is important to identify miRNAs that modulate the Ras/ERK pathway during breast carcinogenesis and progression. The Ras GTPase superfamily member RERG (Ras-related and estrogen-regulated growth inhibitor) acts as a tumor suppressor to reduce breast cancer cell proliferation and tumor formation and has been suggested to have a regulatory role in the Ras/ERK pathway. In this study, we found that RERG exerted its tumor suppressor role by attenuating the activation of Ras/ERK signaling effectors. Furthermore, we found that miR-382-5p directly targets and represses RERG to attenuate the inhibitory effects of RERG on the oncogenic Ras/ERK pathway. Thereby, miR-382-5p promoted breast cancer cell viability, clonogenicity, survival, migration, invasion and in vivo tumorigenesis/metastasis. In clinical interpretation, miR-382-5p expression was negatively correlated with RERG expression, and it also significantly functioned as an independent oncomiR for the higher incidence and poorer prognosis of breast cancer. This novel connection highlights new diagnostic and prognostic roles for miR-382-5p and RERG in breast cancer.